Thiophene derivative ppar modulators

ABSTRACT

The present invention is directed to compounds represented by the following structural formula, Formula I: and stereoisomers, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein: (a) X is selected from the group consisting of O, S, S(O)2, N, and a bond; (b) U is an aliphatic linker wherein one carbon atom of the aliphatic linker may be replaced with O, NH or S, and wherein such aliphatic linker is optionally substituted with R30: (c) Y is selected from the group consisting of C, O, S, NH and a single bond; and (d) E is C(R3)(R4)A or A.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor superfamily, a large and diverse group ofproteins that mediate ligand-dependent transcriptional activation andrepression. Three subtypes of PPARs have been isolated: PPARα, PPARγ andPPARδ.

The expression profile of each isoform differs significantly from theothers, whereby PPARα is expressed primarily, but not exclusively inliver; PPARγ is expressed primarily in adipose tissue; and PPARδ isexpressed ubiquitously. Studies of the individual PPAR isoforms andligands have revealed their regulation of processes involved in insulinresistance and diabetes, as well as lipid disorders, such ashyperlipidemia and dyslipidemia. PPARγ agonists, such as pioglitazone,can be useful in the treatment of non-insulin dependent diabetesmellitus. Such PPARγ agonists are associated with insulin sensitization.

PPARα agonists, such as fenofibrate, can be useful in the treatment ofhyperlipidemia. Although clinical evidence is not available to revealthe utility of PPARδ agonists in humans, several preclinical studiessuggest that PPARδ agonists can be useful in the treatment of diabetesand lipid disorders.

The prevalence of the conditions that comprise Metabolic Syndrome(obesity, insulin resistance, hyperlipidemia, hypertension andatherosclerosis) continues to increase. New pharmaceutical agents areneeded to address the unmet clinical needs of patients.

PPARδ agonists have been suggested as a potential treatment for use inregulating many of the parameters associated with Metabolic Syndrome andAtherosclerosis. For example, in obese, non-diabetic rhesus monkeys, aPPARδ agonist reduced circulating triglycerides and LDL, decreased basalinsulin levels and increased HDL (Oliver, W. R. et al. Proc Natl AcadSci 98:5306-5311; 2001). The insulin sensitization observed with the useof a PPARδ agonist is thought to be in part due to decreased myocellularlipids (Dressel, U. et al. Mol Endocrinol 17:2477-2493; 2003).

Further, atherosclerosis is considered to be a disease consequence ofdyslipidemia and may be associated with inflammatory disease. C-reactiveprotein (CRP) production is part of the acute-phase response to mostforms of inflammation, infection and tissue damage. It is measureddiagnostically as a marker of low-grade inflammation. Plasma CRP levelsof greater than 3 mg/L have been considered predictive of high risk forcoronary artery disease (J. Clin. Invest 111: 1085-1812, 2003).

PPARδ agonists are believed to mediate anti-inflammatory effects.Indeed, treatment of LPS-stimulated macrophages with a PPARδ agonist hasbeen observed to reduce the expression of iNOS, IL12, and IL-6 (Welch,J. S. et al. Proc Natl Acad Sci 100:6712-67172003).

It may be especially desirable when the active pharmaceutical agentselectively modulates a PPAR receptor subtype to provide an especiallydesirable pharmacological profile. In some instances, it can bedesirable when the active pharmacological agent selectively modulatesmore than one PPAR receptor subtype to provide a desired pharmacologicalprofile.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by thefollowing structural Formula I′:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl,        and C3-C6 cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkyl is        optionally substituted with from one to three substituents        independently selected from R1′; and further wherein C₁-C₈        alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with        from one to three substituents independently selected from R2;    -   (b) R1′ are each independently selected from the group        consisting of hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,        C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16,        R17; R18, R19, R20, R21, R22, R23, R24 and R25 are each        independently selected from the group consisting of hydrogen,        C₁-C₆ alkyl and aryl;    -   (c) R2, R26, R27, R28, and R31 are each independently selected        from the group consisting of hydrogen, hydroxy, cyano, nitro,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₃-C₆        haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy,        aryl-C₀₋₄-alkyl, heteroaryl, heterocycloalkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂;    -   (d) X is selected from the group consisting of O, S, S(O)₂, N        and a bond;    -   (e) U is an aliphatic linker wherein one carbon atom of the        aliphatic linker is optionally replaced with C, NH or S, and        wherein such aliphatic linker is optionally substituted with        from one to four substituents each independently selected from        R30;    -   (f) Y is selected from the group consisting of C, NH, and a        single bond;    -   (g) E is C(R3)(R4)A or A and wherein        -   (i) A is selected from the group consisting of carboxyl,            tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide and            acylsulfonamide; wherein sulfonamide, acylsulfonamide and            tetrazole are each optionally substituted with from one to            two groups independently selected from R⁷;        -   (ii) each R⁷ is independently selected from the group            consisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl            and C₁-C₆ alkyl;        -   (iii) R3 is selected from the group consisting of hydrogen,            C₁-C₅ alkyl, and C₁-C₅ alkoxy; and        -   (iv) R⁴ is selected from the group consisting of H, C₁-C₅            alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl            C₀-C₄ alkyl, and R3 and R4 are optionally combined to form a            C₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and            aryl-alkyl are each optionally substituted with one to three            each independently selected from R26;        -   with the proviso that when R1 is C₁-C₈ alkyl, Y is in a para            substituted position with relation to X, and X is selected            from the group consisting of a bond and O, then R4 is            selected from the group consisting of C₁-C₅ alkoxy, aryloxy,            and arylC₀-C₄ alkyl; with the additional proviso that when            R1 is C₁-C₈ alkyl, Y is in a para substituted position with            relation to X, X is S, and U is optionally substituted            methylene, then R4 is selected from the group consisting of            C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl;    -   (h) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (i) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl,        C₁-C₆ allyl, and OR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl        are each optionally substituted with from one to three        independently selected from R27; R29 is selected from the group        consisting of hydrogen and C₁-C₄ alkyl;    -   (j) R10, R11 are each independently selected from the group        consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆        haloalkyloxy, C₃-C₇ cycloalkyl, aryl-C₀₋₄-alkyl,        aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, aryloxy, C(O)R13′, COOR14′,        OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18′C(O)R19′, NR20′SO₂R21′,        SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and wherein        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three independently selected from        R28;    -   (k) R12′, R12″, R13′, R14′, R15′, R16′, R17′, R18′, R19′, R20′,        R21′, R22′, R23′, R24′, and R25′ are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl and aryl; and    -   (l) R30 is selected from the group consisting of C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three substituents each        independently selected from R31. A further embodiment of the        present invention is a compound of the Formula I″:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkyl is        optionally substituted with from one to three substituents        independently selected from R1′; and further wherein C₁-C₈        alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with        from one to three substituents independently selected from R2;    -   (b) R1′ are each independently selected from the group        consisting of hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,        C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16,        R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each        independently selected from the group consisting of hydrogen,        C₁-C₆ alkyl and aryl;    -   (c) R2, R26, R27, R28, and R31 are each independently selected        from the group consisting of hydrogen, hydroxy, cyano, nitro,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, C₁-C₆haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy,        aryl-C₀₋₄-alkyl, heteroaryl, heterocycloalkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂;    -   (d) X is selected from the group consisting of O, S, S(O)₂, N        and a bond;    -   (e) U is an aliphatic linker wherein one carbon atom of the        aliphatic linker is optionally replaced with O, NH or S, and        wherein such aliphatic linker is substituted with from one to        four substituents each independently selected from R³⁰;    -   (f) Y is selected from the group consisting of C, O, S, NH and a        single bond;    -   (g) E is C(R3)(R4)A or A and wherein        -   (i) A is selected from the group consisting of carboxyl,            tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide and            acylsulfonamide; wherein sulfonamide, acylsulfonamide and            tetrazole are each optionally substituted with from one to            two groups independently selected from R⁷;        -   (ii) each R⁷ is independently selected from the group            consisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl            and C₁-C₆ alkyl;        -   (iii) R³ is selected from the group consisting of hydrogen,            C₁-C₅ alkyl, and C₁-C₅ alkoxy; and        -   (iv) R⁴ is selected from the group consisting of H, C₁-C₅            alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl            C₀-C₄ alkyl, and R3 and R4 are optionally combined to form a            C₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and            aryl-alkyl are each optionally substituted with one to three            each independently selected from R26;        -   with the proviso that when R1 is C₁-C₈ alkyl, Y is in a para            substituted position with relation to X, and X is selected            from the group consisting of a bond and O, then R4 is            selected from the group consisting of C₁-C₈ alkoxy, aryloxy,            and arylC₀-C₄ alkyl; with the additional proviso that when            R1 is C₁-C₈ alkyl, Y is in a para substituted position with            relation to X, X is S, and U is optionally substituted            methylene, then R4 is selected from the group consisting of            C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl;    -   (h) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (i) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl,        C₁-C₆ alkyl, and OR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl        are each optionally substituted with from one to three        independently selected from R27; R29 is selected from the group        consisting of hydrogen and C₁-C₄ alkyl;    -   (j) R10, R11 are each independently selected from the group        consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆        haloalkyloxy, C₃-C₇ cycloalkyl, aryl-C₀₋₄-alkyl,        aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, aryloxy, C(O)R13′, COOR14′,        OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18′C(O)R19′, NR20′SO₂R21′,        SR22′, S(c)R23′, S(O)₂R24′, and S(Q)₂N(R25′)₂; and wherein        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three independently selected from        R28;    -   (k) R12′, R12″, R13′, R14′, R15′, R16′, R17′, R18′, R19′, R20′,        R21′, R22′, R23′, R24′, and R25′ are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl and aryl; and    -   (l) R30 is selected from the group consisting of C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three substituents each        independently selected from R31.

Yet another embodiment of the present invention is a compound of theFormula I′″:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkyl is        optionally substituted with from one to three substituents        independently selected from R1′; and further wherein C₁-C₈        alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C3-C6        cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with        from one to three substituents independently selected from R2;    -   (b) R1′ are each independently selected from the group        consisting of hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,        C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16,        R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each        independently selected from the group consisting of hydrogen,        C₁-C₆ alkyl and aryl;    -   (c) R2, R26, R27, R28, and R31 are each independently selected        from the group consisting of hydrogen, hydroxy, cyano, nitro,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy,        aryl-C₀₋₄-alkyl, heteroaryl, heterocycloalkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂;    -   (d) X is selected from the group consisting of O, S, S(O)₂, N        and a bond;    -   (e) U is an aliphatic linker wherein one carbon atom of the        aliphatic linker is optionally replaced with O, NH or S, and        wherein such aliphatic linker is optionally substituted with        from one to four substituents each independently selected from        R³⁰;    -   (f) Y is selected from the group consisting of C, O, S, NH and a        single bond;    -   (g) E is C(R³)(R⁴)A or A and wherein        -   (i) A is selected from the group consisting of carboxyl,            tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide and            acylsulfonamide; wherein sulfonamide, acylsulfonamide and            tetrazole are each optionally substituted with from one to            two groups independently selected from R⁷;        -   (ii) each R⁷ is independently selected from the group            consisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl            and C₁-C₆ alkyl;        -   (iii) R3 is selected from the group consisting of hydrogen,            C₁-C₅ alkyl, and C₁-C₅ alkoxy; and        -   (iv) R4 is selected from the group consisting of H, C₁-C₅            alkyl, C₁-C₈ alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl            C₀-C₄ alkyl, and R3 and R4 are optionally combined to form a            C₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and            aryl-alkyl are each optionally substituted with one to three            each independently selected from R26;        -   with the proviso that when R1 is C₁-C₈ alkyl, Y is in a para            substituted position with relation to X, and X is selected            from the group consisting of a bond and O, then R4 is            selected from the group consisting of C₁-C₅ alkoxy, aryloxy,            and arylC₀-C₄ alkyl; with the additional proviso that when            R1 is C₁-C₁₀ alkyl, Y is in a para substituted position with            relation to X, X is S, and U is optionally substituted            methylene, then R4 is selected from the group consisting of            C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl;        -   with the further proviso that when Y is O then R4 is            selected from the group consisting of C₁-C₅ alkyl, C₁-C₅            alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl C₀-C₄ alkyl, and            R3 and R4 are optionally combined to form a C₃-C₄            cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and            aryl-alkyl are each optionally substituted with one to three            each independently selected from R26;    -   (h) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (i) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl,        C₁-C₆ allyl, and OR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl        are each optionally substituted with from one to three        independently selected from R27; R29 is selected from the group        consisting of hydrogen and C₁-C₄ alkyl;    -   (j) R10, R11 are each independently selected from the group        consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆        haloalkyloxy, C₃-C₇ cycloalkyl, aryl-C₀₋₄-alkyl,        aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, aryloxy, C(O)R13′, COOR14′,        OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18OC(O)R19′, NR20′SO₂R21′,        SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and wherein        aryl-CO₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three independently selected from        R28;    -   (k) R12′, R12″, R13′, R14′, R15′, R16′, R17′, R18′, R19′, R20′,        R21′, R22′, R23′, R24′, and R25′ are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl and aryl; and    -   (l) R30 is selected from the group consisting of C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three substituents each        independently selected from R31.

An embodiment of the present invention is a compound of the structuralFormula I:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl,        and C3-C6 cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkyl is        optionally substituted with from one to three substituents        independently selected from R1′; and further wherein C₁-C₈        alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with        from one to three substituents independently selected from R2;    -   (b) R1′ are each independently selected from the group        consisting of hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl-COOR12, C₃-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,        C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16,        R17, R18, R19, R20, R21, R22, R23, R24 and R25 are each        independently selected from the group consisting of hydrogen,        C₁-C₆ alkyl and aryl;    -   (c) R2, R26, R27, R28, and R31 are each independently selected        from the group consisting of hydrogen, hydroxy, cyano, nitro,        halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy,        C₁-C₆haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy,        aryl-C₀₋₄-alkyl, heteroaryl, heterocycloalkyl, C(O)R13, COOR14,        OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,        S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂;    -   (d) X is selected from the group consisting of O, S, S(O)₂, N        and a bond;    -   (e) U is an aliphatic linker wherein one carbon atom of the        aliphatic linker may be replaced with O, NH or S, and wherein        such aliphatic linker is optionally substituted with R³⁰;    -   (f) Y is selected from the group consisting of C, O, S, NH and a        single bond;    -   (g) E is C(R³)(R⁴)A or A and wherein        -   (i) A is selected from the group consisting of carboxyl,            tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide and            acylsulfonamide; wherein sulfonamide, acylsulfonamide and            tetrazole are each optionally substituted with from one to            two groups independently selected from R⁷;        -   (ii) each R⁷ is independently selected from the group            consisting of hydrogen, C₂-C₆ haloalkyl, aryl C₀-C₄ alkyl            and C₀-C₆ alkyl;        -   (iii) R³ is selected from the group consisting of hydrogen,            C₁-C₅ alkyl, and C₁-C₅ alkoxy; and        -   (iv) R⁴ is selected from the group consisting of H, C₁-C₅            alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl            C₀-C₄ alkyl, and R³ and R4 are optionally combined to form a            C₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and            aryl-alkyl are each optionally substituted with one to three            each independently selected from R26;        -   with the proviso that when R1 is C₁-C₈ alkyl, Y is in a para            substituted position with relation to X, and X is selected            from the group consisting of a bond and O, then R4 is            selected from the group consisting of C₁-C₅ alkoxy, aryloxy,            and arylC₀-C₄ alkyl; with the additional proviso that when            R1 is C₁-C₈ alkyl, Y is in a para substituted position with            relation to X, X is S, and U is optionally substituted            methylene, then R4 is selected from the group consisting of            C₁-C₅ alkoxy, aryloxy, and arylCO₀—C₄ alkyl;    -   (h) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (i) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl,        C₁-C₆ allyl, and OR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl        are each optionally substituted with from one to three        independently selected from R27; R29 is selected from the group        consisting of hydrogen and C₁-C₄ alkyl;    -   (j) R10, R11 are each independently selected from the group        consisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆        alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆        haloalkyloxy, C₃-C₇ cycloalkyl, aryl-C₀₋₄-alkyl,        aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, aryloxy, C(O)R13′, COOR14′,        OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18′C(O)R19′, NR20′SO₂R21′,        SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and wherein        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three independently selected from        R28;    -   (k) R12′, R12″, R13′, R14′, R15′, R16′, R17′, R18′, R19′, R20′,        R21′, R22′, R23′, R24′, and R25′ are each independently selected        from the group consisting of hydrogen, C₁-C₆ alkyl and aryl; and    -   (l) R30 is selected from the group consisting of C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₆ alkyl,        aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl,        and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are each optionally        substituted with from one to three substituents each        independently selected from R31.

In one embodiment, the present invention also relates to pharmaceuticalcompositions comprising at least one compound of the present invention,or a pharmaceutically acceptable salt, solvate, hydrate, orstereioisomer thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofselectively modulating a PPAR delta receptor by contacting the receptorwith at least one compound represented by Structural Formula I, or apharmaceutically acceptable salt, solvate, hydrate, or stereioisomerthereof.

In another embodiment, the present invention relates to a method ofmodulating one or more of the PPAR alpha, beta, gamma, and/or deltareceptors.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention are believed to be effective intreating and preventing Metabolic syndrome, Type II diabetes,hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension,atherosclerosis, and other disorders related to Metabolic syndrome andcardiovascular diseases. Further, compounds of this invention can beuseful for lowering fibrinogen, increasing HDL levels, treating renaldisease, controlling desirable weight, treating demyelinating diseases,treating certain viral infections, and treating liver disease. Inaddition, the compounds can be associated with fewer clinical sideeffects than compounds currently used to treat such conditions.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings.

As used herein, the term “aliphatic linker” or “aliphatic group” is anon-aromatic, consisting solely of carbon and hydrogen and mayoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds (also refer herein as “alkenyl” and “alkynyl”). Analiphatic or aliphatic group may be straight chained, branched (alsorefer herein as “alkyl”) or cyclic (also refer herein as “cycloalkyl).When straight chained or branched, an aliphatic group typically containsbetween about 1 and about 10 carbon atoms, more typically between about1 and about 6 carbon atoms. When cyclic, an aliphatic typically containsbetween about 3 and about 10 carbon atoms, more typically between about3 and about 7 carbon atoms. Aliphatics are preferably C₁-C₁₀ straightchained or branched alkyl groups (i.e. completely saturated aliphaticgroups), more preferably C₁-C₆ straight chained or branched alkylgroups. Examples include, but are not limited to methyl, ethyl, propyl,n-propyl, iso-propyl, n-butyl, sec-butyl, and tert-butyl. Additionalexamples include, but are not limited to, cyclopropyl, cyclopentyl,cyclohexyl, cyclopentyl, cyclohexylyl and the like. It can be apreferred embodiment of the present invention that one carbon atom ofthe aliphatic linker is replaced with an O, NH, or S. It may further bepreferred that the aliphatic linker is substituted with from one to foursubstituents each independently selected from R30. It may be preferredthat the aliphatic linker is substituted with two substituents eachindependently selected from R30.

The term “alkyl,” unless otherwise indicated, refers to those alkylgroups of a designated number of carbon atoms of either a straight orbranched saturated configuration. As used herein, “C₀ alkyl” means thatthere is no carbon and therefore represents a bond. Examples of “alkyl”include, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, isopentyland the like. Alkyl as defined above may be optionally substituted witha designated number of substituents as set forth in the embodimentrecited above. As used herein, the term “alkyloxo” means an alkyl groupof the designated number of carbon atoms with a “═O” substituent.

The term “alkenyl” means hydrocarbon chain of a specified number ofcarbon atoms of either a straight or branched configuration and havingat least one carbon-carbon double bond, which may occur at any pointalong the chain, such as ethenyl, propenyl, butenyl, pentenyl, vinyl,alkyl, 2-butenyl and the like. Alkenyl as defined above may beoptionally substituted with designated number of substituents as setforth in the embodiment recited above.

The term “alkynyl” means hydrocarbon chain of a specified number ofcarbon atoms of either a straight or branched configuration and havingat least one carbon-carbon triple bond, which may occur at any pointalong the chain. Example of alkynyl is acetylene. Alkynyl as definedabove may be optionally substituted with designated number ofsubstituents as set forth in the embodiment recited above.

The term “heteroalkyl” refers to a means hydrocarbon chain of aspecified number of carbon atoms wherein at least one carbon is replacedby a heteroatom selected from the group consisting of O, N and S.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle containing one or more rings of from 3 to 12 carbon atoms,typically 3 to 7 carbon atoms. Examples of cycloalkyl includes, but arenot limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl, and the like. “Cycloalkyaryl” means that an aryl is fusedwith a cycloalkyl, and “Cycloalkylaryl-alkyl” means that thecycloalkylaryl is linked to the parent molecule through the alkyl.Cycloalkyl as defined above may be optionally substituted with adesignated number of substituents as set forth in the embodiment recitedabove.

The term “halo” refers to fluoro, chloro, bromo and iodo.

The term “haloalkyl” is a C₁-C₆ alkyl group, which is substituted withone or more halo atoms selected from F, Br, Cl and I. An example of ahaloalkyl group is trifluoromethyl (CF₃); however, the term is in no waylimited to trifluoromethyl. Trihalomethyl can be a preferred haloalkylgroup.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached through an oxygen bridge, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like. Alkoxyas defined above may be optionally substituted with a designated numberof substituents as set forth in the embodiment recited above.

The term “haloalkyloxy” represents a C₁-C₆ haloalkyl group attachedthrough an oxygen bridge, such as OCF₃. The “haloalkyloxyl” as definedabove may be optionally substituted with a designated number ofsubstituents as set forth in the embodiment recited above.

The term “aryl” includes carbocyclic aromatic ring systems (e.g.phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl). “Aryl” as defined abovemay be optionally substituted with a designated number of substituentsas set forth in the embodiment recited above. A preferred aryloxy groupcan be phenoxy, wherein the 0 is linked to the parent molecule.

The term “arylalkyl” refers to an aryl alkyl group which is linked tothe parent molecule through the alkyl group, which may be furtheroptionally substituted with a designated number of substituents as setforth in the embodiment recited above. One preferred arylalkyl group canbe benzyl or phenyl. When arylalkyl is arylcoalkyl, then the aryl groupis bonded directly to the parent molecule. Likewise, arylheteroalkylmeans an aryl group linked to the parent molecule through theheteroalkyl group.

The term “acyl” refers to alkylcarbonyl species.

The term “heteroaryl” group, as used herein, is an aromatic ring systemhaving at least one heteroatom such as nitrogen, sulfur or oxygen andincludes monocyclic, bicyclic or tricyclic aromatic ring of 5- to14-carbon atoms containing one or more heteroatoms selected from thegroup consisting of O, N, and S. The “heteroaryl” as defined above maybe optionally substituted with a designated number of substituents asset forth in the embodiment recited above. Examples of heteroaryl are,but are not limited to, furanyl, indolyl, thienyl (also referred toherein as “thiophenyl”) thiazolyl, imidazolyl, isoxazoyl, oxazoyl,pyrazoyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl andpurinyl, cinnolinyl, benzofuranyl, benzothienyl, benzotriazolyl,benzoxazolyl, quinoline, isoxazolyl, isoquinoline and the like. The term“heteroarylalkyl” means that the heteroaryl group is linked to theparent molecule through the alkyl portion of the heteroarylalkyl.

The term “heterocycloalkyl” refers to a non-aromatic ring which containsone or more oxygen, nitrogen or sulfur and includes a monocyclic,bicyclic or tricyclic non-aromatic ring of 5 to 14 carbon atomscontaining one or more heteroatoms selected from O, N or S. The“heterocycloalkyl” as defined above may be optionally substituted with adesignated number of substituents as set forth in the embodiment recitedabove. Examples of heterocycloalkyl include, but are not limited to,morpholine, piperidine, piperazine, pyrrolidine, and thiomorpholine. Asused herein, alkyl groups include straight chained and branchedhydrocarbons, which are completely saturated.

As used herein, the phrase “selectively modulate” means a compound whoseEC50 for the stated PPAR receptor is at least ten fold lower than itsEC50 for the other PPAR receptor subtypes.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated usingmethods familiar to the skilled artisan. The present invention includeseach diastereoisomer of compounds of Structural Formula I and mixturesthereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

“Pharmaceutically-acceptable salt” refers to salts of the compounds ofthe Structural Formula I which are considered to be acceptable forclinical and/or veterinary use. Typical pharmaceutically-acceptablesalts include those salts prepared by reaction of the compounds of thepresent invention with a mineral or organic acid or an organic orinorganic base. Such salts are known as acid additional salts and baseaddition salts, respectively. It will be recognized that the particularcounterion forming a part of any salt of this invention is not of acritical nature, so long as the salt as a whole ispharmaceutically-acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole. These salts maybe prepared by methods known to the skilled artisan.

The compounds of Structural Formula I may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

Certain compounds of Structural Formula I may exist in different stableconformational forms that may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

The term, “active ingredient” means the compounds generically describedby Structural Formula I as well as the sterioisomers, salts, solvates,and hydrates,

The term “pharmaceutically acceptable” means that the carrier, diluent,excipients and salt are pharmaceutically compatible with the otheringredients of the composition. Pharmaceutical compositions of thepresent invention are prepared by procedures known in the art using wellknown and readily available ingredients.

“Preventing” refers to reducing the likelihood that the recipient willincur or develop any of the pathological conditions described herein.The term “preventing” is particularly applicable to a patient that issusceptible to the particular patholical condition.

“Treating” refers to mediating a disease or condition and preventing, ormitigating, its further progression or ameliorate the symptomsassociated with the disease or condition.

“Pharmaceutically-effective amount” means that amount of activeingredient, that will elicit the biological or medical response of atissue, system, or mammal. Such an amount can be administeredprophylactically to a patient thought to be susceptible to developmentof a disease or condition. Such amount when administeredprophylactically to a patient can also be effective to prevent or lessenthe severity of the mediated condition. Such an amount is intended toinclude an amount which is sufficient to modulate a selected PPARreceptor or to prevent or mediate a disease or condition. Generally, theeffective amount of a Compound of Formula I will be between 0.02 through5000 mg per day. Preferably the effective amount is between 1 through1,500 mg per day. Preferably the dosage is from 1 through 1,000 mg perday.

The desired dose may be presented in a single dose or as divided dosesadministered at appropriate intervals.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cardiovascular disease, for raising serum HDLcholesterol levels, for lowering serum triglyceride levels and for lowerserum LDL cholesterol levels. Elevated triglyceride and LDL levels, andlow HDL levels, are risk factors for the development of heart disease,stroke, and circulatory system disorders and diseases.

The compounds and compositions of the present invention are also usefulfor treating and/or preventing obesity.

Further, these compounds and compositions are useful for the treatmentand/or prophylaxis of non-insulin dependent diabetes mellitus (NIDDM)with reduced or no body weight gains by the patients. Furthermore, thecompounds and compositions of the present invention are useful to treator prevent acute or transient disorders in insulin sensitivity, such assometimes occur following surgery, trauma, myocardial infarction, andthe like. The physician of ordinary skill will know how to identifyhumans who will benefit from administration of the compounds andcompositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective amount of active ingredient, asdefined herein, to a hyperglycemic human or non-human mammal in needthereof.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating a PPARreceptor mediated condition.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingMetabolic syndrome, diabetes, treating obesity, lowering tryglyceridelevels, lowering serum LDL levels, raising the plasma level of highdensity lipoprotein, and for treating, preventing or reducing the riskof developing atherosclerosis, and for preventing or reducing the riskof having a first or subsequent atherosclerotic disease event inmammals, particularly in humans. In general, a therapeutically effectiveamount of a compound of the present invention typically reduces serumtriglyceride levels of a patient by about 20% or more, and increasesserum HDL levels in a patient. Preferably, HDL levels will be increasedby about 30% or more. In addition, a therapeutically effective amount ofa compound, used to prevent or treat NIDDM, typically reduces serumglucose levels, or more specifically HbAlc, of a patient by about 0.7%or more.

When used herein Metabolic syndrome includes pre-diabetic insulinresistance syndrome and the resulting complications thereof, insulinresistance, non-insulin dependent diabetes, dyslipidemia, hyperglycemiaobesity, coagulopathy, hypertension and other complications associatedwith diabetes. The methods and treatments mentioned herein include theabove and encompass the treatment and/or prophylaxis of any one of orany combination of the following: pre-diabetic insulin resistancesyndrome, the resulting complications thereof, insulin resistance, TypeII or non-insulin dependent diabetes, dyslipidemia, hyperglycemia,obesity and the complications associated with diabetes includingcardiovascular disease, especially atherosclerosis.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition which contains a compound of Structural Formula I, astereoisomer, salt, solvate and/or hydrate thereof (“Active Igredient”)and one or more additional active agents, as well as administration of acompound of Active Ingredient and each active agent in its own separatepharmaceutical dosage formulation. For example, an Active Ingredient andan insulin secretogogue such as biguanides, thiazolidinediones,sulfonylureas, insulin, or α-glucosidose inhibitors can be administeredto the patient together in a single oral dosage composition such as atablet or capsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, an ActiveIngredient and one or more additional active agents can be administeredat essentially the same time, i.e., concurrently, or at separatelystaggered times, i.e., sequentially; combination therapy is understoodto include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein an Active Ingredient is administered in combination with oneor more of the following active agents: antihyperlipidemic agents;plasma HDL-raising agents; antihypercholesterolemic agents, fibrates,vitamins, aspirin, and the like. As noted above, the Active Ingredientcan be administered in combination with more than one additional activeagent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the Active Ingredient can be effectivelyused in combination with, for example, sulfonylureas, biguanides,thiazolidinediones, α-glucosidase inhibitors, other insulinsecretogogues, insulin as well as the active agents discussed above fortreating atherosclerosis.

The Active Ingredients of the present invention, have valuablepharmacological properties and can be used in pharmaceuticalcompositions containing a therapeutically effective amount of ActiveIngredient of the present invention, in combination with one or morepharmaceutically acceptable excipients. Excipients are inert substancessuch as, without limitation carriers, diluents, fillers, flavoringagents, sweeteners, lubricants, solubilizers, suspending agents, wettingagents, binders, disintegrating agents, encapsulating material and otherconventional adjuvants. Proper formulation is dependent upon the routeof administration chosen. Pharmaceutical compositions typically containfrom about 1 to about 99 weight percent of the Active Ingredient of thepresent invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theActive Ingredient of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1500 milligrams or more according to the particular treatmentinvolved. It may be preferred that the unit dosage is from about 1 mg toabout 1000 mg.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Advantageously, compositions containing the compound of StructuralFormula I or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of Structural Formula I actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

Solid form formulations include powders, tablets and capsules.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

The following pharmaceutical formulations 1 and 2 are illustrative onlyand are not intended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg.

In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new selective PPAR receptor agonists.

The compounds of the present invention can be useful for modulatinginsulin secretion and as research tools. Certain compounds andconditions within the scope of this invention are preferred. Thefollowing conditions, invention embodiments, and compoundcharacteristics listed in tabular form are preferred features and may beindependently combined to produce a variety of preferred compounds andprocess conditions. The following list of embodiments of this inventionis not intended to limit the scope of this invention in any way.

Some preferred characteristics of compounds of formula I are:

-   -   (a) R3 is methyl;    -   (b) R4 is hydrogen;    -   (c) R3 and R4 are each hydrogen;    -   (d) R3 and R4 are each methyl;    -   (e) A is carboxyl;    -   (f) X is —O—;    -   (g) X is —S—;    -   (h) X is a bond;    -   (i) U is CH;    -   (j) U is CH₂CH;    -   (k) U is substituted with arylC₁-C₄alkyl;    -   (l) R9 is methyl;    -   (m) R9 is hydrogen;    -   (n) R9 is C₁-C₃ alkyl;    -   (o) R8 is methyl;    -   (p) R8 and R9 are each hydrogen;    -   (g) R10 is CF₃;    -   (r) R10 is haloalkyl;    -   (s) R10 is haloalkyloxy;    -   (t) R11 is hydrogen    -   (u) R10 and R11 are each hydrogen;    -   (v) R11 is haloalkyl;    -   (w) R1 is substituted C₁-C₄ alkyl;    -   (x) R1 is hydrogen;    -   (y) Y is O;    -   (z) Y is S;    -   (aa) Y is C;    -   (bb) E is C(R3)(R4)A;    -   (cc) R3 is hydrogen;    -   (dd) R3 is C₁₋₂₂ alkyl;    -   (ee) R⁴ is C₁-C₂ alkyl;    -   (ff) R4 is selected from the group consisting of alkoxy and        aryloxy;    -   (gg) A is COOH;    -   (hh) Aliphatic linker is saturated;    -   (ii) Aliphatic linker is substituted with C₁-C₃ alkyl;    -   (jj) Aliphatic linker is substituted with arylC₁-C₄alkyl;    -   (kk) Aliphatic linker is C₁-C₃ alkyl;    -   (ll) Aliphatic linker is C₁-C₂ alkyl;    -   (mm) Aliphatic linker is C₂-C₃ alkyl and one carbon is replaced        with an —O—;    -   (nn) Aliphatic linker is C₁-C₃ alkyl and one carbon is replaced        with an —S—;    -   (oo) Aryl is a phenyl group;    -   (pp) A compound of Formula I that selectively modulates a delta        receptor;    -   (qq) An Active Ingredient, as described herein, that is a PPAR        coagaonist that modulates a gamma receptor and a delta receptor;    -   (rr) An Active Ingredient, as described herein, for use in the        treatment of cardiovascular disease;    -   (ss) An Active Ingredient, as described herein, for use in the        treatment of Metabolic syndrome;    -   (tt) An Active Ingredient for use in the control of obesity;    -   (uu) An Active Ingredient for use in treating diabetes;    -   (vv) An Active Ingredient that is a PPAR receptor agonist;    -   (ww) A compound of Formula I wherein the headpiece of Formula I        is:

-   -   (xx) A compound of Formula I selected from the group consisting        of        (2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-acetic        acid,        (2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-acetic        acid,        3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenyl)-propionic        acid, and        (3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-acetic;    -   (yy) A compound of Formula I that is        (3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-acetic;    -   (zz) A compound of Formula I selected from the group consisting        of:

Compound Name

3-{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-phenyl}-propionic acid

{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-phenoxy}-acetic acid

3-{2-Methyl-4-[3-phenyl-5- (4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]- phenyl}-propionic acid

3-{4-[3,5-Bis-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-2-methyl-phenyl}-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- propoxy}-phenyl)-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- butoxy}-phenyl)-propionic acid

3-(2-Methyl-4-{2-methyl-1- [3-methyl-5-(4- trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}- phenyl)-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2- phenyl-ethoxy}-phenyl)- propionic acid

3-(4-{1-[3-(2-Hydroxy- ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- ethylsulfanyl}-2-methyl- phenyl)-propionic acid

Synthesis

Compounds of the present invention have been formed as specificallydescribed in the examples. Further, many compounds are prepared as moregenerally using a) alkylation of phenol/thiophenol with a halide, b) aMitsunobu protocol (O. Mitsunobu, 1981 Synthesis, p1); c) and othermethods known to the skilled artisan. Alternative synthesis methods mayalso be effective and known to the skilled artisan.

For example, an intermediate like A is alkylated with an alkylatingagent B in the presence of a base (e.g. K2CO3, Cs2CO3 etc.). Hydrolysisin the presence of aqueous NaOH or LiOH gave the acid product.

Alternatively, an intermediate like A is coupled with an alcohol C underMitsunobu reaction condition (DEAD/PPh3, ADDP/Pbu3 etc.). Hydrolysis inthe presence of aqueous NaOH or LiOH gave the acid product:

Thioether analogs could also be prepared by a ZnI2 mediated thioetherformation reaction as shown below:

3-Substituted thiophene analogs can be made by the following schemes:

Thiophene intermediates B and C can be made in one of the followingmethods:

EXEMPLIFICATION

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way.

Instrumental Analysis

Infrared spectra are recorded on a Perkin Elmer 781 spectrometer. ¹H NMRspectra are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the δ scale, multiplicity(b=broad, s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR are recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the δ scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-D₆ at 39.5 ppm). Combustionanalyses are performed by Eli Lilly & Company MicroanalyticalLaboratory. High resolution mass spectra are obtained on VG ZAB 3F or VG70 SE spectrometers. Analytical thin layer chromatography is performedon EM Reagent 0.25 mm silica gel 60-F plates. Visualization isaccomplished with UV light.

Preparation 1 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic Acid

Step A 2-(4-Benzyloxy-2-formylphenoxy)-2-methyl Propionic Acid EthylEster

5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch.Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethylbromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0mmol) in dry DMF (25 mL) are heated at 80° C. for 18 h. The reactionmixture is cooled and partitioned between water (30 mL) and ether (75mL). The organic layer is washed with brine (15 mL). The aqueous layersare back-extracted with ethyl acetate (30 mL), and the organic layer iswashed with brine (20 mL). The combined organic layers are dried(Na₂SO₄) and concentrated to a brown oil. The crude product is purifiedby flash chromatography using hexanes:ethyl acetate (2.5:1) to give apale yellow solid (3.04 g, 89%): mp 65° C.; ¹H NMR (400 MHz, CDCl₃) δ1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d,1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES)m/e 343.1 [M+1].

Step B 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic Acid EthylEster

2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester(9.00 g, 26.3 mmol) in ethanol (250 mL) is treated with 5% Pd/C (1.25 g)and hydrogen (60 psi, rt, overnight). Additional 5% Pd/C (1.25 g) isadded, and the reaction is continued for 6 h at 40° C. The mixture isfiltered and concentrated to a tan oil (6.25 g). This oil contained 9mol % of 2-(4-Hydroxy-2-hydroxymethyl-phenoxy)-2-methyl-propionic acidethyl ester. ¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 1.51 (s,6H), 2.14 (s, 3H), 4.24 (q, 2H, J=7.3 Hz), 5.68 (brs, 1H), 6.47 (dd, 1H,J=3.4, 8.8 Hz), 6.59 (d, 1H, J=8.3 Hz), 6.60 (brs, 1H).

The following compound is prepared in a similar manner:

Preparation 2 2-(4-Hydroxy-2-methyl-phenoxy)-acetic Acid

¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, 3H, J=7.1 Hz), 2.24 (s, 3H), 4.25 (q,2H, J=7.1 Hz), 4.55 (s, 2H), 6.56 (dd, 1H, J=2.7, 8.5 Hz), 6.61 (d, 1H,J=8.3 Hz), 6.65 (d, 2H, J=2.9 Hz).

Preparation 3 (4-Hydroxy-2-propyl-phenoxy)-acetic Acid Ethyl Ester

Step A 4-Benzyloxy-2-propylphenol

2-Allyl-4-benzyloxyphenol (WO 9728137 A1 19970807, Adams, A. D. et al.)(5.00 g, 20.8 mmol) in ethyl acetate (40 mL) is treated with 5% Pd/C(0.25 g) and hydrogen (1 atm) at ambient temperature for 18 h. Themixture is filtered and concentrated. The crude product is purified on aBiotage medium pressure chromatography system using a 40 L normal phasecartridge and eluted with 10% ethyl acetate in hexanes to give a tansolid (2.8 g, 56%). Rf=0.33 (25% EtOAc/Hexanes); ¹H NMR (400 MHz, CDCl₃)δ 7.44-7.31 (m, 5H) 6.78 (s, 1H), 6.69 (d, J=1.5 Hz, 2H), 5.00 (s, 2H),4.31 (s, 1H), 2.55 (t, J=7.6 Hz, 2H), 1.64 (q, J=7.5 Hz, 2H), 0.97 (t,J=7.3 Hz, 3H).

Step B (4-Benzyloxy-2-propylphenoxy)acetic Acid Ethyl Ester

A solution of 4-benzyloxy-2-propylphenol (0.50 g, 1.94 mmol) in dry DMF(7 mL) is cooled in an ice bath and treated with NaH (0.15 g, 3.8 mmol,60% oil dispersion). The ice bath is removed, ethyl bromoacetate (0.43mL, 3.9 mmol) is added, and the mixture is placed in an oil bath (T=85°C.). After 18 h, the reaction mixture is cooled and concentrated invacuo. The residue is diluted with EtOAc, washed with brine (2×), dried(Na₂SO₄), and concentrated. The crude product is purified by radialchromatography using 10% ethyl acetate in hexanes to give a tan solid(0.62 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31 (m, 5H), 6.82 (d,J=2.9 Hz, 1H), 6.72 (dd, J=8.8, 2.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H),5.00 (s, 2H), 4.57 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.63 (t, J=7.6 Hz,2H), 1.64 (q, J=7.5 Hz, 2-H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz,3H); MS (FIA) m/e 329 (M+1).

Step C (4-Hydroxy-2-propylphenoxy)acetic Acid Ethyl Ester

A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C (75 mg) andhydrogen (60 psi) at ambient temperature for 24 h. The mixture isfiltered and concentrated. The crude product is purified by radialchromatography using 15% ethyl acetate in hexanes to give a tan solid(0.25 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 6.66 (d, J=2.9 Hz, 1H), 6.62(d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s,1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz,2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239(M+1).

Preparation 4 (3-Bromo-4-hydroxy-phenoxy)-acetic Acid Ethyl Ester

To a solution of (4-hydroxy-phenoxy)-acetic acid ethyl ester (0.59 g, 3mmol) in acetic acid (1.5 mL) is added bromine (0.48 g, 9 mmol) inacetic acid (0.5 mL) at room temperature. After 5 min, solvent isevaporated and purified by column chromatography on silica gel givingthe title compound (0.6 g).

Preparation 5 (4-Mercapto-Phenoxy)-acetic Acid Ethyl Ester

Step A (4-Chlorosulfonyl-phenoxy)-acetic Acid Ethyl Ester

Phenoxy-acetic acid ethyl ester (9.1 mL) is added to chlorosulfonic acid(15 mL) at 0° C. dropwise. The reaction is stirred at 0° C. for 30 min,it is allowed to warm to room temperature. After 2 hrs, the reactionmixture is poured into ice, solid product is collected by filtration anddried under vacuum.

Step B (4-Mercapto-phenoxy)-acetic Acid Ethyl Ester

To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98g, 3.5 mmol) and tin powder (2.1 g) in ethanol (4.4 mL) is added HCl indioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to refluxfor 2 hrs, it is poured into ice and methylene chloride and filtered.The layers are separated and extracted with methylene chloride, driedand concentrated. The crude product is used for next step withoutpurification.

The following compounds are made in a similar manner:

Preparation 6 (4-Mercapto-2-methyl-phenoxy)-acetic Acid Ethyl Ester

This compound can also be made by the following procedure: To a stirredsuspension of Zn powder (10 μm, 78.16 g, 1.2 mol) and dichlorodimethylsilane (154.30 g, 145.02 mL, 1.2 mol) in 500 mL of dichloroethane isadded a solution of (4-chlorosulfonyl-2-methyl-phenoxy)-acetic acidethyl ester (100 g, 0.34 mol) and 1,3-dimethylimidazolidin-2-one (116.98g, 112.05 mL, 1.02 mol) in 1 L of DCE. Addition is at a rate so as tomaintain the internal temperature at ˜52° C., cooling with chilled wateras necessary. After addition is complete, the mixture is heated at 75°C. for 1 hour. It is then cooled to room temperature, filtered andconcentrated iv. Add MTBE, washed twice with saturated LiCl solutionconcentrate iv again. Take up the residue in CH₃CN, wash with hexane(4×) and concentrate iv to yield a biphasic mixture. Let stand in aseparatory funnel and separate layers, keeping the bottom layer forproduct. Filtration through a plug of silica gel (1 Kg, 25%EtOAc/hexane) and subsequent concentration yields 61 g (79%) of a clear,colorless oil.

NMR (DMSO-d₆) δ 7.1 (s, 1H), 7.05 (dd, 1H), 6.75 (d, 1H), 5.03 (s, 1H),4.75 (s, 2H), 4.15 (q, 2H), 2.15 (s, 3H), 1.2 (t, 3H).

Preparation 7 (4-Mercapto-2-propyl-phenoxy)-acetic Acid Ethyl Ester

Preparation 8 3-(4-Hydroxy-2-methyl-phenyl)-propionic Acid Methyl Ester

Step A 4-Bromo-3-methyl-phenyl Benzyl Ester

To a solution of 4-Bromo-3-methyl-phenol (20.6 g, 0.0.11 mol) in DMF(100 mL) is added Cs2CO3 (54 g, 0.165 mol), followed by benzyl bromide(14.4 mL). After stirred at 60° C. for 40 h, the reaction mixture isdiluted with ethyl acetate, filtered through celite. The filtrate iswashed with water and brine, dried over sodium sulfate, concentrationyields the title product (27 g).

Step B 3-(4-Benzyloxy-2-methyl-phenyl)-propionic Acid Methyl Ester

To a solution of 4-bromo-3-methyl-phenyl benzyl ester (7.6 g, 27.4 mmol)in propronitrile (200) mL) is added methyl acrylate (10 mL) anddiisopropylethyl amine (9.75 mL), the solution is degassed and filledwith nitrogen for three times. To this mixture are addedtri-o-tolyl-phosphane (3.36 g) and palladium acetate (1.25 g) undernitrogen, then heated at 110° C. overnight, cooled to room temperature,filtered through celite. The solvent is evaporated, the residue is takeninto ethyl acetate and washed with water and brine, dried over sodiumsulfate. Concentration and column chromatography on silica gel elutedwith hexanes and ethyl acetate yields the title compound (6.33 g).

Step C 3-(4-Hydroxy-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(4-Benzyloxy-2-methyl-phenyl)-propionic acid methyl ester(13.7 g, 48.5 mmol) and Pd/C (5%, 13.7 g) in MeOH (423 mL) is stirredunder 60 psi of hydrogen for 24 hrs. Catalyst is filtered off, filtrateis concentrated giving the title compound (8.8 g, 93.5%).

Preparation 9 3-(4-Mercapto-2-methyl-phenyl)-propionic Acid Methyl Ester

Step A 3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic AcidMethyl Ester

3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.0 g, 25.75mmol) is dissolved into dry dioxane (100 mL) and combined with4-dimethylamino pyridine (0.500 g, 2.6 mmol), triethylamine (7.0 mL,51.5 mmol), and dimethylaminothiocarbomoyl chloride (4.5 g, 32.17 mmol).The reaction is heated to reflux under nitrogen. The reaction ismonitored by TLC until all of the phenol is consumed, 20 h. Aftercooling to room temperature, the reaction is diluted with ethyl acetate(200 mL). Water (75 mL) is added and the two layers are separated. Theorganic layer is washed with brine (75 mL) then dried over anhydroussodium sulfate. The solvent is removed and the residue is dried undervacuum.

Step B 3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic AcidMethyl Ester

3-(4-Dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acid methylester, taken crude from the previous step, is diluted with 75 mL oftetradecane and heated to reflux under nitrogen. The reaction ismonitored by TLC until all the conversion is complete, 20 h. Thereaction is allowed to cool to room temperature, then the tetradecane isdecanted away from the resulting oil. The residue is rinsed severaltimes with hexanes. This oil is then purified using flash columnchromatography, yielding 5.01 g, or 69% (2 steps) of the product.

Step C 3-(4-Mercapto-2-methyl-phenyl)-propionic Acid Methyl Ester

3-(4-Dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methylester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and to thisis added sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol). Thereaction is heated to reflux under nitrogen and monitored by TLC. Aftercomplete conversion, 20 h., the reaction is allowed to cool to roomtemperature. The reaction is neutralized with 1N HCl (7.23 mL) anddiluted with ethyl acetate (150 mL). The two phases are separated andthe organic layer is washed with water (75 mL), then brine (75 mL). Theorganic layer is then dried over anhydrous sodium sulfate, thenconcentrated to yield 4.43 g crude product that is used without furtherpurification.

Preparation 10 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic acid

Step A 4-Bromo-3-methyl-benzoic Acid Benzyl Ester

To a solution of 4-Bromo-3-methyl-benzoic acid benzyl (25.3 g, 0.118mol) in DMF (200 mL) is added Cs2CO3 (76.6 g, 0.235 mol), followed bybenzyl bromide (15.4 mL). After stirred at room temperature for 2 h, thereaction mixture is diluted with ethyl acetate, filtered through celite.The filtrate is washed with water and brine, dried over sodium sulfate,concentration yields the title product.

Step B 4-(2-Methoxycarbonyl-vinyl)-3-methyl-benzoic Acid Benzyl Ester

To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester (36 g, 118mmol) in propronitrile (1000 mL) is added methyl acrylate (43.3 mL) anddiisopropylethyl amine (42 mL), the solution is degassed and filled withnitrogen for three times. To this mixture are addedtri-o-tolyl-phosphane (14.5 g) and palladium acetate (5.34 g) undernitrogen, then heated at 110° C. overnight, cooled to room temperature,filtered through celite. The solvent is evaporated, the residue is takeninto ethyl acetate and washed with water and brine, dried over sodiumsulfate. Concentration and column chromatography on silica gel elutedwith hexanes and ethyl acetate yields the title compound (31 g, 84.7%).

Step C 4-(2-Methoxycarbonyl-ethyl)-3-methyl-benzoic Acid

A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzylester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) andmethanol (100 mL) is stirred under 60 psi of hydrogen overnight.Catalyst is filtered off, filtrate is concentrated giving the titlecompound (8.3 g, 100%).

Preparation 11 (4-Hydroxy-2-methyl-phenyl)-acetic Acid Methyl Ester

Step A

4-Methoxy-2-methylbenzoic acid (2.5 g, 15.04 mmol) is stirred in thionylchloride (50 mL) at reflux 2 hr. The mixture is concentrated and dilutedwith toluene (10 mL) and concentrated. The resulting solid is driedunder vacuum 18 hr. The resulting acid chloride is stirred in 20 mLether at 0 deg C. A solution of diazomethane (39.6 mmol) in ether (150mL) is added to the acid chloride solution and stirred 18 hr. Theresulting diazoketone solution is concentrated. The residue is stirredin methanol (100 mL) and a solution of silver benzoate in triethylamine(1.0 g in 10 mL) is added and the reaction is heated to 60 deg C. andstirred 1 hr. The mixture is concentrated, diluted with 1.0 N aqueoushydrochloric acid (20 mL), extracted to three portions of ethyl acetate(50 mL each). The extracts are combined, washed with aqueous saturatedsodium hydrogen carbonate, water, and brine (50 mL each), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue ispurified via silica gel chromatography eluting with 9:1 hexanes:ethylacetate to afford 1.5 g (51%) of the homologated ester as a white solid.

Step B

(4-Methoxy-2-methyl-phenyl)-acetic acid methyl ester (1.5 g, 7.72 mmol)is stirred in dichloromethane (50 mL) at 0 deg. C. Aluminum chloride(4.13 g, 31 mmol) is added followed by ethane thiol (2.9 mL, 38.6 mmol).The resulting mixture is stirred at room temperature for 2 hr. Water (50mL) is added and the product is extracted into ethyl acetate (3×50 ml),the extracts are combined, dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the title compound as a colorlessoil, 1.4 g, 100%. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 12 (3-Hydroxy-phenyl)-acetic Acid Methyl Ester

Step A (3-Hydroxy-phenyl)-acetic Acid Methyl Ester

(3-Hydroxy-phenyl)-acetic acid (5.0 g, 32.86 mmol) is stirred inmethanol (100 mL) and concentrated (98%) sulfuric acid (3.0 mL) isadded. The mixture is heated to reflux 18 hr. The reaction is cooled andconcentrated. The residue is diluted with water (100 mL) and extractedwith ethyl acetate (3×50 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, and concentrated to yield thetitle compound as an orange oil, 5.46 g, 100%. MS M⁺+1 167. Thestructure is confirmed by ¹H NMR spectroscopy.

The following compounds are made in a similar manner:

Preparation 13 (3-Hydroxy-4-methoxy-phenyl)-acetic Acid Methyl Ester

An orange oil. MS M⁺+1 197. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 14 3-(3-Hydroxy-phenyl)-propionic Acid Methyl Ester

Step A 3-(3-Hydroxy-phenyl)-propionic Acid Methyl Ester

An orange oil. MS M⁺+1 181. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 15 (3-Mercapto-phenyl)-acetic Acid Methyl Ester

Step A (3-Dimethylthiocarbamoyloxy-phenyl)-acetic Acid Methyl Ester

A mixture of (3-Hydroxy-phenyl)-acetic acid methyl ester (5.5 g, 33.1mmol), N,N-dimethyl thiocarbamoyl chloride (5.11 g, 41.38 mmol),triethylamine (9.2 mL, 66.2 mmol), N,N-dimethylamino pyridine (0.4 g,3.31 mmol) and dioxane (50 mL) is stirred at reflux 18 hr. The mixtureis concentrated, partioned between 1M aqueous hydrochloric acid (200 mL)and ethyl acetate (3×75 mL). The combined organic extracts are driedover anhydrous magnesium sulfate, filtered, concentrated, and purifiedvia silica chromatography eluting the product with dichloromethane toafford the title compound as a brown oil, 6.8 g, 81%. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step B (3-Dimethylcarbamoylsulfanyl-phenyl)-acetic Acid Methyl Ester

(3-Dimethylthiocarbamoyloxy-phenyl)-acetic acid methyl ester (6.8 g,26.84 mmol) is stirred in tetradecane (30 mL) at 255 deg C. for 8 hr.The mixture is cooled, the residue is purified by silica chromatographyeluting the product with hexanes to 1:1 hexanes:ethyl acetate to affordthe title compound as an orange oil, 4.9 g, 58 W. MS M⁺+1 254. Thestructure is confirmed by ¹H NMR spectroscopy.

Step C (3-Mercapto-phenyl)-acetic Acid Methyl Ester

A mixture of (3-dimethylcarbamoylsulfanyl-phenyl)-acetic acid methylester (2.0 g, 7.9 mmol), potassium hydroxide (1.4 g, 24 mmol) methanol(50 mL), and water (5 mL) is stirred at reflux 3 hr. The mixture isconcentrated, and product partitioned between 1M aqueous hydrochloricacid (50 mL) and ethyl acetate (3×75 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue is taken up in methanol (50 mL), 2 mL concentrated sulfuric acidis added, and the mixture refluxed 3 hr. The mixture is concentrated,and the residue purified by silica chromatography eluting with 7:3hexanes:ethyl acetate to afford the title compound as a pale yellow oil,1.0 g, 69%. MS M⁺+1 183. The structure is confirmed by ¹H NMRspectroscopy.

Preparation 16 3-(4-Iodomethyl-2-methyl-phenyl)-propionic Acid MethylEster

Step A 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic Acid Methyl Ester

A mixture of methyl-4-bromo-3-methylbenzoate (5.7 g, 24.88 mmol),lithium aluminum hydride (29 mL, 29 mmol, 1 M solution intetrahydrofuran) and tetrahydrofuran (100 mL) is stirred in ice/waterfor 1 hr. The reaction is quenched with aqueous hydrochloric acid (50mL, 1 M). The product is extracted into ethyl acetate (3×100 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The crude product is taken up in propionitrile (100mL). Methylacrylate (10 mL, 121.5 mmol), palladium acetate (1.12 g, 5mmol), tri-o-tolylphosphine (3.0 g, 10 mmol), and N,N-diisopropylethylamine (8.7 mL, 50 mmol) are sequentially added and the resultingreaction mixture is heated to 110 deg C. 3 hr. The mixture isconcentrated, and the residue diluted with aqueous hydrochloric acid(100 mL, 1M). The product is extracted with dichloromethane (2×100 mL)and ethyl acetate (100 mL). The combined extracts are dried overanhydrous magnesium sulfate, filtered, concentrated, and purified viasilica chromatography eluting with 7:3 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate to afford the pure product as a yellow oil, 4.7 g,91%. MS M⁺+1 207. The structure is confirmed by ¹H NMR spectroscopy.

Step B 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methylester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and tetrahydrofuran(618 mL) is shaken under 60 psig. Hydrogen 24 hr. The catalyst isfiltered off, and the mixture is concentrated to afford the product as apale yellow oil, 4.3 g, 91%. The structure is confirmed by ¹H NMRspectroscopy.

Step C 3-(4-Iodomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) anddichloromethane (10 mL) is stirred at room temperature. A solution ofiodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the blackmixture is stirred at room temperature 2 hr. The brown mixture isdiluted with 10% aqueous sodium hydrogen sulfite (5 mL) and theresulting clear mixture is washed with ethyl acetate (3×50 mL). Thecombined extracts are dried over anhydrous magnesium sulfate, filteredand concentrated. The residue is purified via silica chromatographyeluting with 9:1 hexanes:ethyl acetate to afford the title compound as acrystalline ivory solid, 0.68 g, 72%. MS M⁺+1 319. The structure isconfirmed by ¹H NMR spectroscopy.

Preparation 17 (4-Bromo-2-methyl-phenoxy)-acetic Acid Methyl Ester

Step A (4-Bromo-2-methyl-phenoxy)-acetic Acid Methyl Ester

A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride(0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), andmethyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at roomtemperature 18 hr. The mixture is diluted with water (50 mL) and theproduct extracted to ethyl acetate (3×50 mL). The combined extracts aredried over anhydrous magnesium sulfate, filtered, concentrated andpurified via silica chromatography eluting with 8:2 hexanes:ethylacetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M⁺259. The structure is confirmed by ¹H NMR spectroscopy.

Preparation 18 3-(4-Amino-2-methyl-phenyl)-propionic Acid Methyl Ester

Step A 3-(2-Methyl-4-nitro-phenyl)-acrylic Acid Methyl Ester

To a solution of 2-bromo-5-nitrotoluene (3.11 g, 14.39 mmol) inpropionitrile (105 mL) is added DIPEA (5.1 mL, 29.28 mmol). The mixtureis degassed three times. Methyl acrylate (5.2 mL, 57.74 mmol) is addedand the mixture is degassed. Tri-o-tolylphosphine (1.77 g, 5.82 mmol)and Pd(OAc)₂ (0.64 g, 2.85 mmol) are added and the mixture is degassed afinal two times followed by heating at 110° C. for 4 h. Upon cooling,the mixture is passed through Celite and the filtrate is concentrated.The residue is partitioned between Et₂O and 1N HCl. The organics arewashed with saturated NaHCO₃ and brine, and dried with Na₂SO₄. The crudematerial is purified by flash chromatography to yield the title compound(2.90 g, 91%).

Step B 3-(4-Amino-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(2-Methyl-4-nitro-phenyl)-acrylic acid methyl ester (1.47g, 6.64 mmol) and 5% Pd/C (0.29 g) in MeOH (100 mL) is exposed to ahydrogen atmosphere (60 psi) for 12 h. The mixture is filtered throughCelite and purified by flash chromatography to yield the title compound(0.99 g, 77%).

Preparation 19 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic AcidMethyl Ester TFA Salt

Step A 3-(4-Formyl-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methylester (0.49 g, 2.35 mmol) and MnO₂ (0.80 g, 9.20 mmol) in chloroform (5mL) is stirred at RT for 4 days. The mixture is filtered through Celite;the Celite is washed with copious amounts of EtOAc. The filtrate isconcentrated and purified by flash chromatography to yield the titlecompound (0.29 g, 60%).

Step B 3-(2-Methyl-4-methylaminomethyl-phenyl)-propionic Acid MethylEster Trifluoroacetic Acid

To a mixture of 3-(4-Formyl-2-methyl-phenyl)-propionic acid methyl ester(0.27 g, 1.31 mmol) and methylamine (2M in THF, 0.60 mL, 1.20 mmol) inanhydrous CH₂Cl₂ (10 mL) is added 4 Å molecular sieves followed byacetic acid (0.090 mL, 1.57 mmol). The mixture is stirred at RT for 1.5h. Sodium triacetoxyborohydride (0.39 g, 1.85 mmol) is added, and themixture is stirred overnight. The reaction is quenched with saturatedNaHCO₃. The organics are washed with saturated NaHCO₃ and brine, anddried with MgSO₄. Upon concentration, the mixture is purified by reversephase chromatography to yield the title compound (0.12 g, 45%).

Preparation 20 3-(4-Aminomethyl-2-methyl-phenyl)-propionic Acid MethylEster

Step A 3-(4-Chloromethyl-2-methyl-phenyl)-propionic Acid Methyl Ester

To a 0° C. solution of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionicacid methyl ester (1.02 g, 4.90 mmol) in anhydrous CH₂Cl₂ (15 mL) isadded triethylamine (0.75 mL, 5.38 mmol) followed by thionyl chloride(0.40 mL, 5.48 mmol). The mixture is allowed to warm to RT overnight.Water is added, and the mixture is extracted with CH₂Cl₂. The organicsare dried with MgSO₄ and concentrated. The crude material is purified byflash chromatography to yield the title compound (1.01 g, 91%).

Step B 3-(4-Azidomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester

To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acidmethyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide(0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added,and the mixture is extracted with EtOAc. The organics are dried withNa₂SO₄ and concentrated to yield the title compound (0.49 g, 91%). Thematerial is used without further purification.

Step C 3-(4-Aminomethyl-2-methyl-phenyl)-propionic Acid Methyl Ester

A mixture of 3-(4-Azidomethyl-2-methyl-phenyl)-propionic acid methylester (0.20 g, 0.86 mmol) and 5% Pd/C (32 mg) in EtOH (50 mL) is exposedto a hydrogen atmosphere (60 psi) at RT overnight. Upon filtering themixture through Celite, the filtrate is concentrated to yield the titlecompound (0.14 g, 78%). The material is used without furtherpurification.

Preparation 21 2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene

Step A 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde

To a mixture of 4-(trifluoromethyl)phenyl-boronic acid (5.18 g, 27.3mmole), 5-bromo-2-thiophenecarboxyaldehyde (5.39 g, 27.3 mmole) andcesium fluoride (14.5 g, 95.5 mmole) in dioxane (100 mL), is bubbledwith nitrogen gas for 15 minutes. The catalyst PdCl₂(dppf) (0.52 g) isthen added to the mixture. The reaction is heated under reflux for 16hours. The solvent is removed on rota vapor, and the resulting residueis partitioned between ethyl acetate (500 ml) and water (500 mL). Theaqueous layer is extracted with more ethyl acetate (100 mL). Thecombined organic solution is washed with brine (3×500 mL), dried overNa₂SO₄ and concentrated. The crude product is purified on a silica gelcolumn, eluting with 0-15% ethyl acetate in hexane and concentrated toprovide the titled compound as yellow solid.

Step B [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

To a solution of 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde(3.02 g, 11.8 mmole) in THF (100 mL), is added to LiBH₄ (1.75 g, 80.24mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15minutes and warmed up to room temperature for 1 hour. The reaction isquenched using 5N HCl (100 mL) at 0° C. The THF is removed on rotavapor, the aqueous solution is then extracted with ethyl acetate (2×100mL). The combined organic solution is washed with brine (3×200 mL),dried over Na₂SO₄ and concentrated. The crude product is purified on asilica gel column, eluting with 20% ethyl acetate in hexane andconcentrated to provide the titled compound as off-white solid.

Step C 2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene

To a mixture of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol(1.52 g, 5.89 mmole) and triethyl amine (1.64 mL, 11.78 mmole) in DCM(100 mL) at 0° C., is injected methanesulfonyl chloride (0.91 mL, 11.78mmole) dropwise. The reaction is kept at 0° C. for an hour and warmed upto room temperature for an hour. The reaction mixture is concentrated onrota vapor, and the resulting residue is purified on a silica gelcolumn, eluting with 0-15% ethyl acetate in hexane and concentrated toprovide the titled compound as off-white solid.

Preparation 22 [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

Step A 3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde

To a solution of trimethylethylenediamine (0.296 mL, 2.28 mmole) in THFat −78° C., is injected 2.0M n-butyllithium in cyclohexane (1.14 mL,2.28 mmole) dropwise. The mixture is stirred for 15 minutes, then addeda solution of 5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde(0.530 g, 2.07 mmole) in THF (5 mL) and stirred for another 15 minutes.To the resulting mixture is injected 2.0M n-butyllithium in cyclohexane(1.55 ml, 3.10 mmole) at −78° C. and warmed up to −18° C. for an hour.The reaction is cooled down to −78° C. again, quenched with excessamount of iodomethane (0.644 mL, 10.35 mmole) and allowed to warm up toroom temperature, then poured into well stirred ice-water (30 mL). Theaqueous solution is then extracted with ethyl acetate (2×30 mL). Thecombined organic solution is washed with brine (3×30 mL), dried overNa₂SO₄ and concentrated. The crude product is purified on a silicagel-column, gradient eluting with 0-20% ethyl acetate in hexane andconcentrated to provide the titled compound as yellow crystalline.

Step B

To a solution of3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.140 g,0.518 mmole) in THF (5 mL), is added to LiBH₄ (0.056 g, 2.57 mmole) inone portion at 0° C. The reaction is kept at 0° C. for 15 minutes andwarmed up to room temperature for 1 hour. The reaction is quenched using1N HCl (10 mL) at 0° C. The THF is removed on rota vapor, the aqueoussolution is then extracted with ethyl acetate (2×10 mL). The combinedorganic solution is washed with brine (3×20 mL), dried over Na₂SO₄ andconcentrated. The crude product is purified on a silica gel column,eluting with 20% ethyl acetate in hexane and concentrated to provide thetitled compound as white solid.

Preparation 231-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol

To a solution of3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.130 g,0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in ethyl ether(0.27 mL, 0.810 mmole) dropwise. The reaction is stirred for 2 hours.The reaction is quenched with saturated NH₄Cl_((aq)) (10 mL), then theaqueous solution is extracted with ethyl acetate (3×15 mL). The combinedorganic solution is washed with brine (3×50 mL), dried over Na₂SO₄ andconcentrated. The crude product is purified on a silica gel column,eluting with 0-20% ethyl acetate in hexane and concentrated to providethe titled compound as yellow solid.

The following compounds are made in a similar manner:

Preparation 24[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

Preparation 251-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol

Preparation 261-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Preparation 271-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-butan-1-ol

Preparation 282-Methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Preparation 291-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-phenyl-ethanol

Preparation 30[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

Step A 2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid

The titled compound is prepared from5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10 mmole)and trimethyl borate (5.68 g, 50.0 mmole) in a similar manner to3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde.

Step B3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde

To a mixture of2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid (0.330 g,1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and cesium fluoride(0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled with nitrogen gasfor 15 minutes. The catalyst PdCl₂(dppf) (0.033 g) is then added to themixture. The reaction is heated under reflux for 16 hours. The solventis removed on rota vapor, and the resulting residue is partitionedbetween ethyl acetate (20 ml) and water (20 mL). The aqueous layer isextracted with more ethyl acetate (20 mL). The combined organic solutionis washed with brine (3×50 mL), dried over Na₂SO₄ and concentrated. Thecrude product is purified on a silica gel column, eluting with 0-15%ethyl acetate in hexane and concentrated to provide the titled compoundas pale yellow crystalline.

Step C[3-Isopropenyl-S-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

To a solution of3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde(0.084 g, 0.283 mmole) in THF (3 mL), is added to NaBH₄ (0.023 g, 0.622mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15minutes and warmed up to room temperature for 2 hours. The reaction isquenched using saturated NH₄Cl_((aq)) (20 mL) at 0° C. The THF isremoved on rota vapor, the aqueous solution is then extracted with ethylacetate (2×10 mL). The combined organic solution is washed with brine(3×20 mL), dried over Na₂SO₄ and concentrated to provide the titledcompound as yellow solid, which is used for the next step withoutfurther purification.

Step D [3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

The solution of[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol(0.084 g, 0.282 mmole) is stirred under nitrogen gas in presence of 10%palladium on carbon (0.085 g) for 16 hours. The catalyst is removed byfiltration, and the filtrate is concentrated to provide the titledcompound as white solid, which is used for the next step without furtherpurification.

Preparation 312-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Step A 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone

To a solution of1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (seePreparation 8) (4.40 g, 15.4 mmole), is added MnO₂ (7.88 g, 77.0 mmole)in one portion.

The mixture is heated under reflux for 16 hours, more MnO₂ (7.88 g, 77.0mmole) is added to the reaction and continued to reflux for 4 hours. Themixture is filtered through a celite pad, and the mother liquid isconcentrated. The crude product is purified on a silica gel column,gradient eluting with 0-20% ethyl acetate in hexane and concentrated toprovide the titled compound as yellow solid.

Step B2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde

To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g,10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide(1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To theresulting ylide, is injected into a solution of1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53g, 5.38 mmole). The reaction is stirred for 2 hours, and thenconcentrated on rota vapor. The residue is purified on a silica gelcolumn, eluting with 0-10% ethyl acetate in hexane and concentrated toprovide2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiopheneas brown oil. The generated vinyl ether is treated with concentratedHCl_((aq)) (2 mL) in THF (60 mL) at 60° C. for 2 hours. The solvents areremoved on rota vapor, and the residue is purified on a silica gelcolumn, eluting with 0-20% ethyl acetate in hexane and concentrated toprovide the titled compound as colorless oil.

Step C2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

To a solution of2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde(1.40 g, 4.69 mmole) in THF (20 mL), is added to NaBH₄ (0.266 g, 7.04mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15minutes and warmed up to room temperature for 2 hours. The reaction isquenched using NH₄Cl_((aq)) (50 mL) at 0° C. The THF is removed on rotavapor, the aqueous solution is then extracted with ethyl acetate (2×50mL). The combined organic solution is washed with brine (3×100 mL),dried over Na₂SO₄ and concentrated. The crude product is purified on asilica gel column, gradient eluting with 0-20% ethyl acetate in hexaneand concentrated to provide the titled compound as white solid.

The racemic material is resolved on a Chiralpak AD column (4.6×250 mm).Eluted with 200′ methanol and concentrated the fractions of the fastercomponent to provide pure enantiomer (isomer 1, 100% ee) and slowercomponent to provide another enantiomer (isomer II, >99.5% ee).

Preparation 32 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanol

To a solution of 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g,5.00 mmole) in THF (20 mL), is added to LiBH₄ (0.327 g, 15.0 mmole) inone portion at 0° C. The reaction is kept at 0° C. for 30 minutes andwarmed up to room temperature for 2 hours. The reaction is quenchedusing NH₄Cl_((aq)) (50 mL) at 0° C. The THF is removed on rota vapor,the aqueous solution is then extracted with ethyl acetate (3×50 mL). Thecombined organic solution is dried over Na₂SO₄ and concentrated toprovide the titled compound as white solid, which is used for the nextstep without further purification.

Preparation 331-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol

To a solution of3-methyl-5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.130 g,0.481 mmole) in THF (5 mL), is injected 3.0 M MeMgBr in ethyl ether(0.27 mL, 0.810 mmole) dropwise. The reaction is stirred for 2 hours.The reaction is quenched with saturated NH₄Cl_((aq)) (10 mL), then theaqueous solution is extracted with ethyl acetate (3×15 mL). The combinedorganic solution is washed with brine (3×50 mL), dried over Na₂SO₄ andconcentrated. The crude product is purified on a silica gel column,eluting with 0-20% ethyl acetate in hexane and concentrated to providethe titled compound as yellow solid.

The following compounds (Preparation 34 to 39) are made in a similarmanner:

Preparation 34[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

Preparation 351-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol

Preparation 361-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Preparation 371-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-butan-1-ol

Preparation 382-Methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Preparation 391-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-phenyl-ethanol

Preparation 40[3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

Step A 2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid

The titled compound is prepared from5-(4-Trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (2.70 g, 10 mmole)and trimethyl borate (5.68 g, 50.0 mmole) in a similar manner to3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde(Preparation 2, Step A).

Step B3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde

To a mixture of2-Formyl-5-(4-trifluoromethyl-phenyl)-thiophene-3-boronic acid (0.330 g,1.10 mmole), 2-Bromo-propene (0.399 g, 3.30 mmole) and cesium fluoride(0.585 g, 3.85 mmole) in dioxane (5 mL), is bubbled with nitrogen gasfor 15 minutes. The catalyst PdCl₂(dppf) (0.033 g) is then added to themixture. The reaction is heated under reflux for 16 hours. The solventis removed on rota vapor, and the resulting residue is partitionedbetween ethyl acetate (20 ml) and water (20 mL). The aqueous layer isextracted with more ethyl acetate (20 mL). The combined organic solutionis washed with brine (3×50 mL), dried over Na₂SO₄ and concentrated. Thecrude product is purified on a silica gel column, eluting with 0-15%ethyl acetate in hexane and concentrated to provide the titled compoundas pale yellow crystalline.

Step C[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

To a solution of3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde(0.084 g, 0.283 mmole) in THF (3 mL), is added to NaBH₄ (0.023 g, 0.622mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15minutes and warmed up to room temperature for 2 hours. The reaction isquenched using saturated NH₄Cl_((aq)) (20 mL) at 0° C. The THF isremoved on rota vapor, the aqueous solution is then extracted with ethylacetate (2×10 mL). The combined organic solution is washed with brine(3×20 mL), dried over Na₂SO₄ and concentrated to provide the titledcompound as yellow solid, which is used for the next step withoutfurther purification.

Step D [3-Isopropyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol

The solution of[3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-methanol(0.084 g, 0.282 mmole) is stirred under nitrogen gas in presence of 10%palladium on carbon (0.085 g) for 16 hours. The catalyst is removed byfiltration, and the filtrate is concentrated to provide the titledcompound as white solid, which is used for the next step without furtherpurification.

Preparation 412-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

Step A

1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone

To a solution of1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (seePreparation 2) (4.40 g, 15.4 mmole), is added MnO₂ (7.88 g, 77.0 mmole)in one portion. The mixture is heated under reflux for 16 hours, moreMnO₂ (7.88 g, 77.0 mmole) is added to the reaction and continued toreflux for 4 hours. The mixture is filtered through a celite pad, andthe mother liquid is concentrated. The crude product is purified on asilica gel column, gradient eluting with 0-20% ethyl acetate in hexaneand concentrated to provide the titled compound as yellow solid.

Step B

2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde

To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g,10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide(1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To theresulting ylide, is injected into a solution of1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53g, 5.38 mmole). The reaction is stirred for 2 hours, and thenconcentrated on rota vapor. The residue is purified on a silica gelcolumn, eluting with 0-10% ethyl acetate in hexane and concentrated toprovide2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiopheneas brown oil. The generated vinyl ether is treated with concentratedHCl_((aq)) (2 mL) in THF (60 mL) at 60° C. for 2 hours. The solvents areremoved on rota vapor, and the residue is purified on a silica gelcolumn, eluting with 0-20% ethyl acetate in hexane and concentrated toprovide the titled compound as colorless oil.

Step C2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propan-1-ol

To a solution of2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionaldehyde(1.40 g, 4.69 mmole) in THF (20 mL), is added to NaBH₄ (0.266 g, 7.04mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15minutes and warmed up to room temperature for 2 hours. The reaction isquenched using NH₄Cl_((aq)) (50 mL) at 0° C. The THF is removed on rotavapor, the aqueous solution is then extracted with ethyl acetate (2×50mL). The combined organic solution is washed with brine (3×100 mL),dried over Na₂SO₄ and concentrated. The crude product is purified on asilica gel column, gradient eluting with 0-20% ethyl acetate in hexaneand concentrated to provide the titled compound as white solid.

The racemic material is resolved on a Chiralpak AD column (4.6×250 mm).Eluted with 100% methanol and concentrated the fractions of the fastercomponent to provide pure enantiomer (isomer 1, 100% ee) and slowercomponent to provide another enantiomer (isomer II, >99.5% ee).

Preparation 42 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanol

To a solution of 1-(2-Methyl-5-phenyl-thiophen-3-yl)-ethanone (1.08 g,5.00 mmole) in THF (20 mL), is added to LiBH₄ (0.327 g, 15.0 mmole) inone portion at 0° C. The reaction is kept at 0° C. for 30 minutes andwarmed up to room temperature for 2 hours. The reaction is quenchedusing NH₄Cl_((aq)) (50 mL) at 0° C. The THF is removed on rota vapor,the aqueous solution is then extracted with ethyl acetate (3×50 mL). Thecombined organic solution is dried over Na₂SO₄ and concentrated toprovide the titled compound as white solid, which is used for the nextstep without further purification.

Example 13-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid

Step A

3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid Methyl Ester

To a solution of 2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene(0.210 g, 0.760 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (0.147 g, 0.760 mmole) in acetonitrile (5 mL), is addedcesium carbonate (0.248 mL, 0.760 mmole) in one portion. The reaction isheated at 50° C. overnight, then concentrated. The residue is loaded toa silica gel column, eluted with ethyl acetate in hexane (0-15%) andconcentrated to provide the titled compound as a white solid.

Step B

3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid

3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicacid methyl ester (0.170 g, 0.390 mmole) is treated with a mixture ofNaOH_((aq)) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight.The organic solvents are removed on rota-vapor. The residue is dilutedwith water (10 mL), acidified to pH=2 with 6N HCl_((aq)). Theprecipitate is collected through filtration, washed with cold water (30mL) and dried to provide the titled compound as white solid. MS (ES):419 (M+H)⁻, the structure is also confirmed by proton NMR.

The following compound (Example 2) is made in a similar manner:

Example 2{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenoxy}-aceticacid

MS (ES): 421 (M+H)⁻, the structure is also confirmed by proton NMR.

Synthesis Method for Examples 3-8

Examples 3 through 8 are made substantially as described:

Step A3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid Methyl Ester

To a solution of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol(0.063 g, 0.232 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acidmethyl ester (0.045 g, 0.232 mmole) in toluene (2 mL) at roomtemperature, is added tributylphosphine (0.087 mL, 0.348 mmole) followedby a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.088 g, 0.348mmole) in toluene (2 mL). The reaction is stirred overnight, and thendiluted with hexane (10 mL). The precipitate is removed throughfiltration and the filtrate is concentrated, loaded to a silica gelcolumn, eluted with ethyl acetate in hexane (0-15%) and concentrated toprovide the titled compound as white solid.

Step B3-{2-Methyl-4-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid

3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicacid methyl ester (0.043 g, 0.0959 mmole) is treated with a mixture ofNaOH_((aq)) (1 mL)/THF (3 mL)/MeOH (3 mL) at room temperature overnight.The organic solvents are removed on rota-vapor. The residue is dilutedwith water (10 mL), acidified to pH=2 with 6N HCl_((aq)). Theprecipitate is collected through filtration, washed with cold water (30mL) and dried to provide the titled compound as a white solid. MS (ES):433 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 33-{2-Methyl-4-[3-phenyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicAcid

MS (ES): 495 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 43-{4-[3,5-Bis-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-2-methyl-phenyl}-propionicAcid

MS (ES): 563 (M+H), the structure is also confirmed by proton NMR.

Example 53-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-propionicAcid

MS (ES): 447 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 63-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-butoxy}-phenyl)-propionicAcid

MS (ES): 461 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 73-(2-Methyl-4-{2-methyl-1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-propionicAcid

MS (ES): 461 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 83-(2-Methyl-4-{1-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-phenyl-ethoxy}-phenyl)-propionicAcid

MS (ES): 509 (M+H)⁻, the structure is also confirmed by proton NMR.

Synthesis Method for Example 9 Step A3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicAcid Methyl Ester

To a solution of1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (1.52 g,3.96 mmole) and 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methylester (0.769 g, 3.96 mmole) in toluene (20 mL) at room temperature, isadded tributylphosphine (1.98 mL, 7.92 mmole) followed by a solution of1,1′-(azodicarbonyl)-dipiperidine (1.99 g, 7.92 mmole) in toluene (20mL). The reaction is stirred overnight, and then diluted with hexane(100 mL). The precipitate is removed through filtration and the filtrateis concentrated, loaded to a silica gel column, eluted with ethylacetate in hexane (0-15%) and concentrated to provide the titledcompound as yellow solid.

Step B3-(2-Methyl-4-{1-[5-(4-trifluoromethyl-phenyl)-3-vinyl-thiophen-2-yl]-ethylsulfanyl}-phenyl)-propionicAcid Methyl Ester

The solution of3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicacid methyl ester (0.195 g, 0.348 mmole) and tributyl(vinyl)tin (0.331g, 1.04 mmole) in toluene (3 mL) is bubbled with nitrogen gas for 10minutes. To it is added tetrakis(triphenylphosphine)palladium(0) (0.020g). The reaction is heated under 80° C. overnight. The mixture isconcentrated, loaded to a silica gel column, eluted with ethyl acetatein hexane (0-15%) and concentrated to provide the titled compound ascolorless oil.

Step C3-(4-{1-[3-(2-Hydroxy-ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicAcid

To a solution of3-(2-Methyl-4-{1-[5-(4-trifluoromethyl-phenyl)-3-vinyl-thiophen-2-yl]-ethylsulfanyl}-phenyl)-propionicacid methyl ester (0.365 g, 0.744 mmole) in THF (5 mL) at 0° C., isadded dropwise 1.0N BH₃/THF complex (3.0 mL, 3.0 mmole). The mixture iswarmed up to room temperature and stirred for an hour. To it is added30% H₂O₂ (10 mL) and 1.0N NaOH_((aq)) (10 mL), and the reaction isheated under reflux for 2 hours. It is then acidified by addingconcentrated HCl carefully to pH=2. The aqueous solution is extractedwith ethyl acetate (3×20 mL), and the combine organic solution is driedand concentrated. The crude product is purified by reverse phasepreparative HPLC, eluting with 5.0 nM NH₄HCO_(3(aq))/CH₃CN andconcentration of fractions to provide the titled compound as a whitesolid.

Example 93-(4-{1-[3-(2-Hydroxy-ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionicAcid

MS (ES): 493 (M+H)⁻, the structure is also confirmed by proton NMR.

Example 10 Isomer II2-Methoxy-3-(4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-propionicAcid

MS (ES): 479 (M+H)⁺, 477 (M+H)⁻, the structure is also confirmed byproton NMR.

Example 11 Isomer II2-Methyl-3-(4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-2-phenoxy-propionicAcid

MS (ES): 572 (M+NH₄)⁺, 553 (M+H), the structure is also confirmed byproton NMR.

Example 12 Isomer I(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-aceticAcid

MS (ES): 481 (M+H)⁺, 479 (M−H)⁻, the structure is also confirmed byproton NMR.

Example 13 Isomer II(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-aceticAcid

MS (ES): 481 (M+H)⁺, 479 (M−H), the structure is also confirmed byproton NMR.

Example 14 Isomer II3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenyl)-propionicAcid

MS (ES): 479 (M+H)⁺, 477 (M−H)⁻, the structure is also confirmed byproton NMR.

Example 15 Isomer II(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-aceticAcid

MS (ES): 435 (M+H)⁺, 433 (M−H) the structure is also confirmed by protonNMR.

Example 16

The newly developed three-step sequence from 2 to 5, affords in anoverall 78% yield (avg. 92% per step).

The final saponification and crystallization proceed without incident.

Compound 1 is obtained in an overall yield of 17%.

3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethylphenyl)thiophen-2-yl]propoxy}phenyl)propionicacid (isomer 2) (1)¹3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethylphenyl)thiophen-2-yl]propoxy}phenyl)propionicacid methyl ester (isomer 2, 398 g, 0.84 mol) is dissolved in THF andMeOH (3800 mL). To the resulting clear yellow solution is added aq. NaOH(335 mL, 1.68 mol) over 15 minutes. The solution is stirred at rt for 2h, then transferred to rotary evaporator and concentrated in vacuo at40° C. to a pale yellow paste. This paste is partitioned between 1N aq.HCl (1700 mL, 1.7 mol) and EtOAc (2000 mL). The aq. layer isback-extracted with EtOAc (2000 mL) and the combined organic layers arewashed with sat'd aq. NaCl (2000 mL), dried (Na₂SO₄), filtered andconcentrated to a pale yellow solid. This solid is recrystallized from amixture of EtOAc (1000 mL) and n-heptane (3000 mL), cooled to 0° C. andfiltered. The solids are rinsed with cold hexanes (1000 mL). The productis dried in vacuo at 45° C. to afford the title compound as a whitecrystalline solid (338 g, 88%). mp: 126.2-132.6° C. ¹H NMR (CDCl₃) δ(dd, 4H, J=25, 8 Hz), 7.14 (s, 1H), 7.07 (d, 1H, J=8 Hz), 6.76 (s, 1H),6.72 (d, 1H, J=8 Hz), 4.08 (t, 1H, J=6 Hz), 3.69 (t, 1H, J=7 Hz), 3.61(m, 1H), 2.91 (t, 2H, J=8 Hz), 2.64 (t, 2H, J=8 Hz), 2.31 (s, 3H), 2.27(s, 3H), 1.49 (d, 3H, J=8 Hz); ¹³C NMR (CDCl₃) δ 179.7, 157.5, 142.5,138.6, 138.2, 137.6, 134.9, 130.9, 129.7, 128.9 (q, J=33 Hz), 127.6,126.0, 125.6, 123.4, 116.9, 112.1, 73.2, 34.9, 34.0, 27.5, 19.7, 19.5,14.2; IR (CHCl₃) 2963, 2923, 1713, 1614, 1502, 1329, 1194, 1120, 1070,823 cm⁻¹; Anal. Calcd. for C₂₅H₂₅F₃O₃S: C, 64.92; H, 5.45; F, 12.32; S,6.93. Found: C, 64.95; H, 5.49; F, 12.05; S, 6.95.

Biological Assays Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARα receptors aredetermined by the procedures detailed below. DNA-dependent binding (ABCDbinding) is carried out using SPA technology with PPAR receptors.Tritium-labeled PPARα agonists are used as radioligands for generatingdisplacement curves and IC₅₀ values with compounds of the invention.Cotransfection assays are carried out in CV-1 cells. The reporterplasmid contained an acylCoA oxidase (AOX) PPRE and TK promoter upstreamof the luciferase reporter cDNA. Appropriate PPARs are constitutivelyexpressed using plasmids containing the CMV promoter. For PPARα,interference by endogenous PPARγ in CV-1 cells is an issue. In order toeliminate such interference, a GAL4 chimeric system is used in which theDNA binding domain of the transfected PPAR is replaced by that of GAL4,and the GAL4 response element is utilized in place of the AOX PPRE.Cotransfection efficacy is determined relative to PPARα agonistreference molecules. Efficacies are determined by computer fit to aconcentration-response curve, or in some cases at a single highconcentration of agonist (10 μM).

These studies are carried out to evaluate the ability of compounds ofthe invention to bind to and/or activate various nuclear transcriptionfactors, particularly huPPARα (“hu” indicates “human”). These studiesprovide in vitro data concerning efficacy and selectivity of compoundsof the invention. Furthermore, binding and cotransfection data forcompounds of the invention are compared with corresponding data formarketed compounds that act on huPPARα.

The binding and cotransfection efficacy values for compounds of theinvention which are especially useful for modulating a PPAR receptor,are ≦100 nM and ≧50%, respectively.

Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation inHuapoAI Transgenic Mice

Compounds of the present invention are studied for effects upon HDL andtriglyceride levels in human apoAI mice. For each compound tested, sevento eight week old male mice, transgenic for human apoAI(C57BL/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.) areacclimated in individual cages for two weeks with standard chow diet(Purina 5001) and water provided ad libitum. After the acclimation, miceand chow are weighed and assigned to test groups (n=5) withrandomization by body weight. Mice are dosed daily by oral gavage for 8days using a 29 gauge, 1½ inch curved feeding needle (Popper & Sons).The vehicle for the controls, test compounds and the positive control(fenofibrate 100 mg/kg) is 1% carboxymethylcellulose (w/v) with 0.25%tween 80 (w/v). All mice are dosed daily between 6 and 8 a.m. with adosing volume of 0.2 ml. Prior to termination, animals and diets areweighed and body weight change and food consumption are calculated.Three hours after last dose, mice are euthanized with CO2 and blood isremoved (0.5-1.0 ml) by cardiac puncture. After sacrifice, the liver,heart, and epididymal fat pad are excised and weighed. Blood ispermitted to clot and serum is separated from the blood bycentrifugation.

Cholesterol and triglycerides are measured calorimetrically usingcommercially prepared reagents (for example, as available from Sigma#339-1000 and Roche #450061 for triglycerides and cholesterol,respectively). The procedures are modified from published work (McGowanM. W. et al., Clin Chem 29:538-542, 1983; Allain C. C. et al., Clin Chem20:470-475, 1974. Commercially available standards for triglycerides andtotal cholesterol, respectively, commercial quality control plasma, andsamples are measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, added to a well containing 200 μl water, provided ablank for each specimen. Plates are incubated at room temperature on aplate shaker and absorbance is read at 500 nm and 540 nm for totalcholesterol and triglycerides, respectively. Values for the positivecontrol are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Serum lipoproteins are separated and cholesterol quantitated by fastprotein liquid chromatography (FPLC) coupled to an in line detectionsystem. Samples are applied to a Superose 6 HR size exclusion column(Amersham Pharmacia Biotech) and eluted with phosphate bufferedsaline-EDTA at 0.5 ml/min. Cholesterol reagent (Roche DiagnosticsChol/HP 704036) at 0.16 ml/min mixed with the column effluent through aT-connection and the mixture passed through a 15 m×0.5 mm id knittedtubing reactor immersed in a 37 C water bath. The colored productproduced in the presence of cholesterol is monitored in the flow streamat 505 nm and the analog voltage from the monitor is converted to adigital signal for collection and analysis. The change in voltagecorresponding to change in cholesterol concentration is plotted vs timeand the area under the curve corresponding to the elution of very lowdensity lipoprotein (VLDL), low density lipoprotein (LDL) and highdensity lipoprotein (HDL) is calculated using Perkin Elmer Turbochromesoftware.

Triglyceride Serum Levels in Mice Dosed with a Compound of the Inventionis Compared to Mice Receiving the Vehicle to identify compounds whichcould be particularly useful for lowering triglycerides. Generally,triglyceride decreases of greater than or equal to 30% (thirty percent)compared to control following a 30 mg/kg dose suggests a compound thatcan be especially useful for lowering triglyceride levels.

The percent increase of HDLc serum levels in mice receiving a compoundof the invention is compared to mice receiving vehicle to identifycompounds of the invention that could be particularly useful forelevating HDL levels. Generally, and increase of greater than or equalto 25% (twenty five percent) increase in HDLc level following a 30 mg/kgdose suggests a compound that can be especially useful for elevatingHDLc levels.

It may be particularly desirable to select compounds of this inventionthat both lower triglyceride levels and increase HDLc levels. However,compounds that either lower triglyceride levels or increase HDLc levelsmay be desirable as well.

Evaluation of Glucose Levels in db/db Mice

The effects upon plasma glucose associated with administering variousdose levels of different compounds of the present invention and the PPARgamma agonist rosiglitazone (BRL49653) or the PPAR alpha agonistfenofibrate, and the control, to male db/db mice, are studied.

Five week old male diabetic (db/db) mice [for example,C57BlKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or leanlittermates are housed 6 per cage with food and water available at alltimes. After an acclimation period of 2 weeks, animals are individuallyidentified by ear notches, weighed, and bled via the tail vein fordetermination of initial glucose levels. Blood is collected (100 μl)from unfasted animals by wrapping each mouse in a towel, cutting the tipof the tail with a scalpel, and milking blood from the tail into aheparinized capillary tube. Sample is discharged into a heparinizedmicrotainer with gel separator and retained on ice. Plasma is obtainedafter centrifugation at 4° C. and glucose measured immediately.Remaining plasma is frozen until the completion of the experiment, whenglucose and triglycerides are assayed in all samples. Animals aregrouped based on initial glucose levels and body weights. Beginning thefollowing morning, mice are dosed daily by oral gavage for 7 days.Treatments are test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse]. On day 7, mice are weighed and bled (tail vein) 3 hoursafter dosing. Twenty-four hours after the 7^(th) dose (i.e., day 8),animals are bled again (tail vein). Samples obtained from consciousanimals on days 0, 7 and 8 are assayed for glucose. After the 24-hourbleed, animals are weighed and dosed for the final time. Three hoursafter dosing on day 8, animals are anesthetized by inhalation ofisoflurane and blood obtained via cardiac puncture (0.5-0.7 ml). Wholeblood is transferred to serum separator tubes, chilled on ice andpermitted to clot. Serum is obtained after centrifugation at 4° C. andfrozen until analysis for compound levels. After sacrifice by cervicaldislocation, the liver, heart and epididymal fat pads are excised andweighed.

Glucose is measured calorimetrically using commercially purchasedreagents. According to the manufacturers, the procedures are modifiedfrom published work (McGowan, M. W., Artiss, J. D., Strandbergh, D. R. &Zak, B. Clin Chem, 20:470-5 (1974) and Keston, A. Specific calorimetricenzymatic analytical reagents for glucose. Abstract of papers 129thMeeting ACS, 31C (1956)); and depend on the release of a mole ofhydrogen peroxide for each mole of analyte, coupled with a colorreaction first described by Trinder (Trinder, P. Determination ofglucose in blood using glucose oxidase with an alternative oxygenacceptor. Ann Clin Biochem, 6:24 (1969)). The absorbance of the dyeproduced is linearly related to the analyte in the sample. The assaysare further modified in our laboratory for use in a 96 well format. Thecommercially available standard for glucose, commercially availablequality control plasma, and samples (2 or 5 μl/well) are measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provided a blankfor each specimen. Plates are incubated at room temperature for 18minutes for glucose on a plate shaker (DPC Micormix 5) and absorbanceread at 500 nm on a plate reader. Sample absorbances are compared to astandard curve (100-800 for glucose). Values for the quality controlsample are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Evaluation of the Effects of compounds of the Present Invention uponA^(y) Mice Body Weight, Fat Mass, Glucose and Insulin Levels FemaleA^(y) Mice

Female A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty weeks ofage the mice are randomly assigned to vehicle control and treated groupsbased on body weight and body fat content as assessed by DEXA scanning(N=6). Mice are then dosed via oral gavage with either vehicle or aCompound of this invention (50 mg/kg) one hour after the initiation ofthe light cycle (for example, about 7 A.M.) for 18 days. Body weightsare measured daily throughout the study. On day 14 mice are maintainedin individual metabolic chambers for indirect calorimetry assessment ofenergy expenditure and fuel utilization. On day 18 mice are againsubjected to DEXA scanning for post treatment measurement of bodycomposition.

The results of p.o. dosing of compound for 18 days on body weight, fatmass, and lean mass are evaluated and suggest which compounds of thisinvention can be especially useful for maintaining desirable weightand/or promoting desired lean to fat mass.

Indirect calorimetry measurements revealing a significant reduction inrespiratory quotient (RQ) in treated animals during the dark cycle[0.864±0.013 (Control) vs. 0.803±0.007 (Treated); p<0.001] is indicativeof an increased utilization of fat during the animals' active (dark)cycle and can be used to selected especially desired compounds of thisinvention. Additionally, treated animals displaying Significantly higherrates of energy expenditure than control animals suggest such compoundsof this invention can be especially desired.

Male KK/A^(y) Mice

Male KK/A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty-two weeksof age the mice are randomly assigned to vehicle control and treatedgroups based on plasma glucose levels. Mice are then dosed via oralgavage with either vehicle or a Compound of this invention (30 mg/kg)one hour after the initiation of the light cycle (7 A.M.) for 14 days.Plasma glucose, triglyceride, and insulin levels are assessed on day 14.

The results of p.o. dosing of compound for 14 days on plasma glucose,triglycerides, and insulin are evaluated to identify compounds of thisinvention which may be especially desired.

Method to Elucidate the LDL-Cholesterol Total-Cholesterol andTriglyceride Lowering Effect

Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120 g areplaced on a high-fat cholesterol-rich diet for two to three weeks priorto use. Feed and water are provided ad libitum throughout the course ofthe experiment. Under these conditions, hamsters becomehypercholesterolemic showing plasma cholesterol levels between 180-280mg/dl. (Hamsters fed with normal chow have a total plasma cholesterollevel between 100-150 mg/dl.) Hamsters with high plasma cholesterol (180mg/dl and above) are randomized into treatment groups based on theirtotal cholesterol level using the GroupOptimizeV211.xls program.

A Compound of this invention is dissolved in an aqueous vehicle(containing CMC with Tween 80) such that each hamster received once aday approx. 1 ml of the solution by garvage at doses 3 and 30 mg/kg bodyweight. Fenofibrate (Sigma Chemical, prepared as a suspension in thesame vehicle) is given as a known alpha-agonist control at a dose of 200mg/kg, and the blank control is vehicle alone. Dosing is performed dailyin the early morning for 14 days.

Quantification of Plasma Lipids:

On the last day of the test, hamsters are bled (400 ul) from thesuborbital sinus while under isoflurane anesthesia 2 h after dosing.Blood samples are collected into heparinized microfuge tubes chilled inice bath. Plasma samples are separated from the blood cells by briefcentrifugation. Total cholesterol and triglycerides are determined bymeans of enzymatic assays carried out automatically in the Monarchequipment (Instrumentation Laboratory) following the manufacturer'sprecedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved byinjecting 25 ul of the pooled plasma samples into an FPLC system elutedwith phosphate buffered saline at 0.5 ml/min through a Superose 6 HR10/30 column (Pharmacia) maintained room temp. Detection andcharacterization of the isolated plasma lipids are accomplished bypostcolumn incubation of the effluent with a Cholesterol/HP reagent (forexample, Roche Lab System; infused at 0.12 ml/min) in a knitted reactioncoil maintained at 37° C. The intensity of the color formed isproportional to the cholesterol concentration and is measuredphotometrically at 505 nm.

The effect of administration of a Compound of this invention for 14 daysis studied for the percent reduction in LDL level with reference to thevehicle group. Especially desired compounds are markedly more potentthan fenofibrate in LDL-lowering efficacy. Compounds of this inventionthat decrease LDL greater than or equal to 30% (thirty percent) comparedto vehicle can be especially desired.

The total-cholesterol and triglyceride lowering effects of a Compound ofthis invention is also studied. The data for reduction in totalcholesterol and triglyceride levels after treatment with a compound ofthis invention for 14 days is compared to the vehicle to suggestcompounds that can be particularly desired. The known controlfenofibrate did not show significant efficacy under the sameexperimental conditions.

Method to Elucidate the Fibrinogen-Lowering Effect of PPAR ModulatorsZucker Fatty Rat Model:

The life phase of the study on fibrinogen-lowering effect of compoundsof this invention is part of the life phase procedures for theantidiabetic studies of the same compounds. On the last (14^(th)) day ofthe treatment period, with the animals placed under surgical anesthesia,˜3 ml of blood is collected, by cardiac puncture, into a syringecontaining citrate buffer. The blood sample is chilled and centrifugedat 4° C. to isolate the plasma that is stored at −70° C. prior tofibrinogen assay.

Quantification of Rat Plasma Fibrinogen:

Rat plasma fibrinogen levels are quantified by using a commercial assaysystem consists of a coagulation instrument following the manufacturer'sprotocol. In essence, 100 ul of plasma is sampled from each specimen anda 1/20 dilution is prepared with buffer. The diluted plasma is incubatedat 37° C. for 240 seconds. Fifty microliters of clotting reagentthrombin solution (provided by the instrument's manufacturer in astandard concentration) is then added. The instrument monitors theclotting time, a function of fibrinogen concentration quantified withreference to standard samples. Compounds that lower fibrinogen levelgreater than vehicle can be especially desired.

Cholesterol and triglyceride lowering effects of compounds of thisinvention are also studied in Zucker rats.

Method to Elucidate the Anti-Body Weight Gain and Anti-Appetite Effectsof Compounds of this Invention

Fourteen-Day Study in Zucker Fatty Rat¹ or ZDF Rat² Models

Male Zucker Fatty rats, non-diabetic (Charles River Laboratories,Wilmington, Mass.) or male ZDF rats (Genetic Models, Inc, Indianapolis,Ind.) of comparable age and weight are acclimated for 1 week prior totreatment. Rats are on normal chow and water is provided ad libitumthroughout the course of the experiment.

Compounds of this invention are dissolved in an aqueous vehicle suchthat each rat received once a day approximately 1 ml of the solution bygarvage at doses 0.1, 0.3, 1 and 3 mg/kg body weight. Fenofibrate (SigmaChemical, prepared as a suspension in the same vehicle) a knownalpha-agonist given at doses of 300 mg/kg, as well as the vehicle arecontrols. Dosing is performed daily in the early morning for 14 days.Over the course of the experiment, body weight and food consumption aremonitored.

Using this assay, compounds of this invention are identified todetermine which can be associated with significant weight reduction.

Method to Elucidate the Activation of the PPAR Delta Receptor In Vivo

This method is particularly useful for measuring the in vivo PPARdeltareceptor activation of compounds of this invention that are determinedto possess significant in vitro activity for that receptor isoform overthe PPAR gamma isoform.

Male PPARa null mice (129s4 SvJae-PPARa<tm1Gonz> mice; JacksonLaboratories) of 8-9 weeks of age are maintained on Purina 5001 chowwith water ad libitum for at least one week prior to use. Feed and waterare provided ad libitum throughout the course of the experiment. Usingthe GroupOptimizeV211.xls program, mice are randomized into treatmentgroups of five animals each based on their body weight.

Compounds of this invention are suspended in an aqueous vehicle of 1%(w/v) carboxymethylcellulose and 0.25% Tween 80 such that each mousereceives once a day approx. 0.2 ml of the solution by gavage at dosesranging from 0.2 to 20 mg/kg body weight. A control group of mice isincluded in each experiment whereby they are dosed in parallel withvehicle alone. Dosing is performed daily in the early morning for 7days.

On the last day of dosing, mice are euthanized by CO2 asphyxiation 3hours after the final dose. Blood samples are collected by heart drawinto EDTA-containing microfuge tubes and chilled on ice. Liver samplesare collected by necropsy and are flash-frozen in liquid nitrogen andstored at −80 degrees Celsius. For RNA isolation from liver, five to tenmg of frozen liver is placed in 700 μl of 1× Nucleic Acid Lysis Solution(Applied Biosystems Inc., Foster City, Calif.) and homogenized using ahand-held tissue macerator (Biospec Products Inc., Bartlesville, Okla.).The homogenate is filtered through an ABI Tissue pre-filter (AppliedBiosystems Inc., Foster City, Calif.) and collected in a deep well plateon an ABI 6100 Nucleic Acid prep station (Applied Biosystems Inc.,Foster City, Calif.). The filtered homogenate is then loaded onto an RNAisolation plate and the RNA Tissue-Filter-DNA method is run on the ABI6100. The isolated RNA is eluted in 150 μl of RNase free water. Forquality assessment, 9 μl of the isolated RNA solution is loaded onto a1% TBE agarose gel, and the RNA is visualized by ethidium bromidefluorescence.

Complementary DNA (cDNA) is synthesized using the ABI High CapacityArchive Kit (Applied Biosystems Inc., Foster City, Calif.). Briefly, a2× reverse transcriptase Master Mix is prepared according to themanufacturer's protocol for the appropriate number of samples (RTBuffer, dNTP, Random Primers, MultiScribe RT (50 U/μl), RNase freewater). For each reaction, 50 μl of 2×RT Master Mix is added to 50 μl ofisolated RNA in a PCR tube that is incubated in a thermocycler (25° C.for 10 minutes followed by 37° C. for 2 hours). The resultant cDNApreparation is diluted 1:100 in dH2O for analysis by real-time PCR.Also, a standard curve of cDNA is diluted 1:20, 1:100, 1:400, 1:2000,1:10,000 for use in final quantitation.

A real-time PCR Master Mix for mouse Cyp4A1 gene expression is mixed tocontain:

-   -   1× Taqman Universal PCR Master Mix (Applied Biosystems Inc.,        Foster City, Calif.)    -   6 micromolar final concentration Forward primer; Qiagen/Operon        Technologies, Alameda, Calif.)    -   6 micromolar final concentration Reverse primer (Qiagen/Operon        Technologies, Alameda, Calif.)    -   0.15 micromolar final concentration Probe (5′ 6-FAM and 3′        Tamra-Q; Qiagen/Operon Technologies, Alameda, Calif.)    -   RNase free water to 10 microliters

A real-time PCR Master Mix for the 18S ribosomal RNA control geneexpression is mixed to contain

-   -   1× Taqman Universal PCR Master Mix (Applied Biosystems Inc.,        Foster City, Calif.)    -   0.34 micromolar Probe/Primer TaqMan® Ribosomal RNA Control        Reagents #4308329 Applied Biosystems Inc., Foster City, Calif.)    -   RNase free water to 10 microliters

For the real-time PCR analysis, 6 ul of the respective Master Mixsolution (either Cyp4A1 or 18S) and 4 ul either of diluted cDNA or ofStandard Curve samples is added to individual wells of a 384-well plate(n=2 for Standards; n=4 for unknowns). Reactions are performed using theABI 7900 HT standard universal RT-PCR cycling protocol. Data areanalyzed using SDS 2.1 (Applied Biosystems Inc., Foster City, Calif.).Average quantity and standard deviation are calculated automatically foreach individual sample, according to the standard curve values. UsingMicrosoft Excel 2000, mean values for each group of five individual miceis calculated. The mean value of each compound-treated group is dividedby the mean value of the vehicle-treated group. The fold induction overthe vehicle group is determined by assigning the vehicle group to thevalue of 1.0, and the fold change of the mean value for each group isexpressed as fold-induction versus vehicle (1.0). Data are plotted usingJandel SigmaPlot 8.0.

Monkey Studies Efficacy Studies

Compounds of the invention may be examined in a dyslipidemic rhesusmonkey model. After an oral dose-escalation study for 28 days in obese,non-diabetic rhesus monkeys a determination of HDL-c elevation is madewith each dose and compared with pretreatment levels. LDL cholesterol isalso determined with each dose. C-reactive protein levels are measuredand compared to pretreatment levels.

Compound of Formula 1 may be shown to elevate plasma HDL-cholesterollevels in an African Green Monkey model in a manner similar to thatdescribed above in rhesus monkeys.

Two groups of monkeys are placed in a dose-escalating study thatconsists of one week of baseline measurements, 9 weeks of treatments(vehicle, Compound of Formula I), and four weeks of washout. Duringbaseline, monkeys in all three groups are administered vehicle oncedaily for seven days. Test compound of Formula I, is administered invehicle once daily for three weeks, then at a greater concentration(double the dose may be desired) once daily for three weeks, and then astill greater concentration (double the most recent dose may be desired)once daily for three weeks. At the completion of treatment, monkeys inboth groups are administered vehicle once daily and monitored for anadditional six weeks.

Animals are fasted overnight and then sedated for body weightmeasurements and blood collection at weeks 1 (vehicle), 2, 3, 4, 6, 7,9, 10, 12, and 14 of the study.

Parameters to measured, for example:

Body weightTotal plasma cholesterol

HDL LDL Triglycerides Insulin Glucose

PK parameters at week 4, 7, and 10 (plasma drug concentration at lastweek of each dose)

ApoAI ApoAII ApoB ApoCIII

Liver enzymes (SGPT, SGOT, □GT)Complete blood count

Additionally, other measures may be made, as appropriate, and consistentwith the stated study design.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound of the Formula 1′:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein: (a) R1 is selected from the group consistingof hydrogen, C₁-C₈ alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl,heteroaryl, and C3-C6 cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkylis optionally substituted with from one to three substituentsindependently selected from R1′; and further wherein C₁-C₈ alkenyl,phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with from oneto three substituents independently selected from R2; (b) R1′ are eachindependently selected from the group consisting of hydroxy, cyano,nitro, halo, oxo, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13,COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24 and R25 are each independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl and aryl; (c) R2,R26, R27, R28, and R31 are each independently selected from the groupconsisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl,C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,C₃-C₇ cycloalkyl, aryloxy, aryl-C₀₋₄-alkyl, heteroaryl,heterocycloalkyl, C(O)R13, COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂,NR18C(O)R19, NR20SO₂R21, SR22, S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; (d)X is selected from the group consisting of O, S, S(O)₂, N and a bond;(e) U is an aliphatic linker wherein one carbon atom of the aliphaticlinker is optionally replaced with O, NH or S, and wherein suchaliphatic linker is optionally substituted with from one to foursubstituents each independently selected from R³⁰; (f) Y is selectedfrom the group consisting of C, NH, and a single bond; (g) E isC(R³)(R⁴)A or A and wherein (i) A is selected from the group consistingof carboxyl, tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide andacylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole areeach optionally substituted with from one to two groups independentlyselected from R⁷; (ii) each R⁷ is independently selected from the groupconsisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl and C₁-C₆alkyl; (iii) R³ is selected from the group consisting of hydrogen, C₁-C₅alkyl, and C₁-C₅ alkoxy; and (iv) R⁴ is selected from the groupconsisting of H, C₁-C₅ alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl,and aryl C₀-C₄ alkyl, and R3 and R4 are optionally combined to form aC₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkylare each optionally substituted with one to three each independentlyselected from R26; with the proviso that when R1 is C₁-C₈ alkyl, Y is ina para substituted position with relation to X, and X is selected fromthe group consisting of a bond and O, then R4 is selected from the groupconsisting of C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; with theadditional proviso that when R1 is C₁-C₈ alkyl, Y is in a parasubstituted position with relation to X, X is S, and U is optionallysubstituted methylene, then R4 is selected from the group consisting ofC₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; (h) R8 is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkylenyl, and halo;(i) R9 is selected from the group consisting of hydrogen, C₁-C₄ alkyl,C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl, C₁-C₆ allyl, andOR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl are each optionallysubstituted with from one to three independently selected from R27; R29is selected from the group consisting of hydrogen and C₁-C₄ alkyl; (j)R10, R11 are each independently selected from the group consisting ofhydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇cycloalkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, aryloxy,C(O)R13′, COOR14′, OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18OC(O)R19′,NR20′SO₂R21′, SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and whereinaryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl are each optionally substituted with from oneto three independently selected from R28; (k) R12′, R12″, R13′, R14′,R15′, R16′, R17′, R18′, R19′, R20′, R21′, R22′, R23′, R24′, and R25′ areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl and aryl; and (l) R30 is selected from the group consisting ofC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and whereinC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are eachoptionally substituted with from one to three substituents eachindependently selected from R31.
 2. A compound of the Formula I″:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein: (a) R1 is selected from the group consistingof hydrogen, C₁-C₈ alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl,heteroaryl, and C3-C6 cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkylis optionally substituted with from one to three substituentsindependently selected from R1′; and further wherein C₁-C₈ alkenyl,phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with from oneto three substituents independently selected from R2; (b) R1′ are eachindependently selected from the group consisting of hydroxy, cyano,nitro, halo, oxo, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆haloalkyl,C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13,COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24 and R25 are each independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl and aryl; (c) R2,R26, R27, R28, and R31 are each independently selected from the groupconsisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl,C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,C₃-C₇ cycloalkyl, aryloxy, aryl-C₀₋₄-alkyl, heteroaryl,heterocycloalkyl, C(O)R13, COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂,NR18C(O)R19, NR20SO₂R21, SR22, S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; (d)X is selected from the group consisting of O, S, S(O)₂, N and a bond;(e) U is an aliphatic linker wherein one carbon atom of the aliphaticlinker is optionally replaced with O, NH or S, and wherein suchaliphatic linker is substituted with from one to four substituents eachindependently selected from R³⁰; (f) Y is selected from the groupconsisting of C, O, S, NH and a single bond; (g) E is C(R³)(R⁴)A or Aand wherein (i) A is selected from the group consisting of carboxyl,tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide andacylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole areeach optionally substituted with from one to two groups independentlyselected from R⁷; (ii) each R⁷ is independently selected from the groupconsisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl and C₁-C₆alkyl; (iii) R³ is selected from the group consisting of hydrogen, C₁-C₅alkyl, and C₁-C₅ alkoxy; and (iv) R⁴ is selected from the groupconsisting of H, C₁-C₅ alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl,and aryl C₀-C₄ alkyl, and R3 and R4 are optionally combined to form aC₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkylare each optionally substituted with one to three each independentlyselected from R26; with the proviso that when R¹ is C₁-C₈ alkyl, Y is ina para substituted position with relation to X, and X is selected fromthe group consisting of a bond and O, then R4 is selected from the groupconsisting of C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; with theadditional proviso that when R¹ is C₁-C₈ alkyl, Y is in a parasubstituted position with relation to X, X is S, and U is optionallysubstituted methylene, then R4 is selected from the group consisting ofC₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; (h) R8 is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkylenyl, and halo;(i) R9 is selected from the group consisting of hydrogen, C₁-C₄ alkyl,C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl, C₁-C₆ allyl, andOR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl are each optionallysubstituted with from one to three independently selected from R27; R29is selected from the group consisting of hydrogen and C₁-C₄ alkyl; (j)R10, R11 are each independently selected from the group consisting ofhydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇cycloalkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, aryloxy,C(O)R13′, COOR14′, OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18OC(O)R19′,NR20′SO₂R21′, SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and whereinaryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl are each optionally substituted with from oneto three independently selected from R28; (k) R12′, R12″, R13′, R14′,R15′, R16′, R17′, R18′, R19′, R20′, R21′, R22′, R23′, R24′, and R25′ areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl and aryl; and (l) R30 is selected from the group consisting ofC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and whereinC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are eachoptionally substituted with from one to three substituents eachindependently selected from R31.
 3. A compound of the Formula I′″:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein: (a) R1 is selected from the group consistingof hydrogen, C₁-C₈ alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl,heteroaryl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkylis optionally substituted with from one to three substituentsindependently selected from R1′; and further wherein C₁-C₈ alkenyl,phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with from oneto three substituents independently selected from R2; (b) R1′ are eachindependently selected from the group consisting of hydroxy, cyano,nitro, halo, oxo, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆haloalkyl,C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13,COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂, NR18C(O)R19, NR20SO₂R21, SR22,S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24 and R25 are each independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl and aryl; (c) R2,R26, R27, R28, and R31 are each independently selected from the groupconsisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl,C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy,C₃-C₇ cycloalkyl, aryloxy, aryl-C₀₋₄-alkyl, heteroaryl,heterocycloalkyl, C(O)R13, COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂,NR18C(O)R19, NR20SO₂R21, SR22, S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; (d)X is selected from the group consisting of O, S, S(O)₂, N and a bond;(e) U is an aliphatic linker wherein one carbon atom of the aliphaticlinker is optionally replaced with O, NH or S, and wherein suchaliphatic linker is optionally substituted with from one to foursubstituents each independently selected from R³⁰; (f) Y is selectedfrom the group consisting of C, O, S, NH and a single bond; (g) E isC(R³)(R⁴)A or A and wherein (i) A is selected from the group consistingof carboxyl, tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide andacylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole areeach optionally substituted with from one to two groups independentlyselected from R⁷; (ii) each R⁷ is independently selected from the groupconsisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl and C₁-C₆alkyl; (iii) R³ is selected from the group consisting of hydrogen, C₁-C₅alkyl, and C₁-C₅ alkoxy; and (iv) R⁴ is selected from the groupconsisting of H, C₁-C₅ alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl,and aryl C₀-C₄ alkyl, and R3 and R4 are optionally combined to form aC₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkylare each optionally substituted with one to three each independentlyselected from R26; with the proviso that when R1 is C₁-C₈ alkyl, Y is ina para substituted position with relation to X, and X is selected fromthe group consisting of a bond and O, then R4 is selected from the groupconsisting of C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; with theadditional proviso that when R1 is C₁-C₈ alkyl, Y is in a parasubstituted position with relation to X, X is S, and U is optionallysubstituted methylene, then R4 is selected from the group consisting ofC₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; with the further provisothat when Y is O then R4 is selected from the group consisting of C₁-C₅alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl, and aryl C₀-C₄ alkyl,and R3 and R4 are optionally combined to form a C₃-C₄ cycloalkyl, andwherein alkyl, alkoxy, cycloalkyl and aryl-alkyl are each optionallysubstituted with one to three each independently selected from R26; (h)R8 is selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄alkylenyl, and halo; (i) R9 is selected from the group consisting ofhydrogen, C₁-C₄ alkyl, C₁-C₄ alkylenyl, halo, aryl-C₀-C₄alkyl,heteroaryl, C₁-C₆ allyl, and OR29, and wherein aryl-C₀-C₄ alkyl,heteroaryl are each optionally substituted with from one to threeindependently selected from R27; R29 is selected from the groupconsisting of hydrogen and C₁-C₄ alkyl; (j) R10, R11 are eachindependently selected from the group consisting of hydrogen, hydroxy,cyano, nitro, halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryl-C₀₋₄-alkyl,aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, aryloxy, C(O)R13′, COOR14′, OC(O)R15′,OS(O)₂R16′, N(R17′)₂, NR18OC(O)R19′, NR20′SO₂R21′, SR22′, S(O)R23′,S(O)₂R24′, and S(O)₂N(R25′)₂; and wherein aryl-C₀₋₄-alkyl,aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl are each optionally substituted with from oneto three independently selected from R28; (k) R12′, R12″, R13′, R14′,R15′, R16′, R17′, R18′, R19′, R20′, R21′, R22′, R23′, R24′, and R25′ areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl and aryl; and (l) R30 is selected from the group consisting ofC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and whereinC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are eachoptionally substituted with from one to three substituents eachindependently selected from R31.
 4. A compound of the Formula I:

and stereoisomers, pharmaceutically acceptable salts, solvates andhydrates thereof, wherein: (a) R1 is selected from the group consistingof hydrogen, C₁-C₈ alkyl, C₁-C₈ alkenyl, phenyl, aryl-C₁₋₄-heteroalkyl,heteroaryl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and wherein C₁-C₈ alkylis optionally substituted with from one to three substituentsindependently selected from R1′; and further wherein C₁-C₈ alkenyl,phenyl, aryl-C₁₋₄-heteroalkyl, heteroaryl, and C3-C6cycloalkylaryl-C₀₋₂-alkyl, are each optionally substituted with from oneto three substituents independently selected from R2; (b) R1′ are eachindependently selected from the group consisting of hydroxy, cyano,nitro, halo, oxo, C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆haloalkyl,C₁-C₆ haloalkyloxy, C₃-C₇ cycloalkyl, aryloxy, aryl-C₁₋₄-alkyl, C(O)R13,COOR14, OC(O)R15, OS(O)₂R16, N(R17)₂, NR8C(O)R19, NR20SO₂R21, SR22,S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; R12, R13, R14, R15, R16, R17, R18,R19, R20, R21, R22, R23, R24 and R25 are each independently selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl and aryl; (c) R2,R26, R27, R28, and R31 are each independently selected from the groupconsisting of hydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl,C₁-C₆ alkyl-COOR12, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkyloxy,C₃-C₇ cycloalkyl, aryloxy, aryl-C₀₋₄-alkyl, heteroaryl,heterocycloalkyl, C(O)R13, COOR14, OC(O)R15, OS(O)₂R16, N(R 17)₂,NR18C(O)R19, NR20SO₂R21, SR22, S(O)R23, S(O)₂R24, and S(O)₂N(R25)₂; (d)X is selected from the group consisting of O, S, S(O)₂, N, and a bond;(e) U is an aliphatic linker wherein one carbon atom of the aliphaticlinker may be replaced with O, NH or S, and wherein such aliphaticlinker is optionally substituted with R³⁰; (f) Y is selected from thegroup consisting of C, O, S, NH and a single bond; (g) E is C(R³)(R⁴)Aor A and wherein (i) A is selected from the group consisting ofcarboxyl, tetrazole, C₁-C₆ alkylnitrile, carboxamide, sulfonamide andacylsulfonamide; wherein sulfonamide, acylsulfonamide and tetrazole areeach optionally substituted with from one to two groups independentlyselected from R⁷; (ii) each R⁷ is independently selected from the groupconsisting of hydrogen, C₁-C₆ haloalkyl, aryl C₀-C₄ alkyl and C₁-C₆alkyl; (iii) R³ is selected from the group consisting of hydrogen, C₁-C₅alkyl, and C₁-C₅ alkoxy; and (iv) R⁴ is selected from the groupconsisting of H, C₁-C₅ alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆ cycloalkyl,and aryl C₀-C₄ alkyl, and R3 and R4 are optionally combined to form aC₃-C₄ cycloalkyl, and wherein alkyl, alkoxy, cycloalkyl and aryl-alkylare each optionally substituted with one to three each independentlyselected from R26; with the proviso that when R¹ is C₁-C₈ alkyl, Y is ina para substituted position with relation to X, and X is selected fromthe group consisting of a bond and O, then R4 is selected from the groupconsisting of C₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; with theadditional proviso that when R1 is C₁-C₈ alkyl, Y is in a parasubstituted position with relation to X, X is S, and U is optionallysubstituted methylene, then R4 is selected from the group consisting ofC₁-C₅ alkoxy, aryloxy, and arylC₀-C₄ alkyl; (h) R8 is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkylenyl, and halo;(i) R9 is selected from the group consisting of hydrogen, C₁-C₄ alkyl,C₁-C₄ alkylenyl, halo, aryl-C₀-C₄ alkyl, heteroaryl, C₁-C₆ allyl, andOR29, and wherein aryl-C₀-C₄ alkyl, heteroaryl are each optionallysubstituted with from one to three independently selected from R27; R29is selected from the group consisting of hydrogen and C₁-C₄ alkyl; (j)R10, R11 are each independently selected from the group consisting ofhydrogen, hydroxy, cyano, nitro, halo, oxo, C₁-C₆ alkyl, C₁-C₆alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkyloxy, C₃-C₇cycloalkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, aryloxy,C(O)R13′, COOR14′, OC(O)R15′, OS(O)₂R16′, N(R17′)₂, NR18OC(O)R19′,NR20′SO₂R21′, SR22′, S(O)R23′, S(O)₂R24′, and S(O)₂N(R25′)₂; and whereinaryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, and C₃-C₆cycloalkylaryl-C₀₋₂-alkyl are each optionally substituted with from oneto three independently selected from R28; (k) R12′, R122″, R13′, R14′,R15′, R16′, R17′, R18′, R19′, R20′, R21′, R22′, R23′, R24′, and R25′ areeach independently selected from the group consisting of hydrogen, C₁-C₆alkyl and aryl; and (l) R30 is selected from the group consisting ofC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl, and whereinC₁-C₆ alkyl, aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl,heteroaryl-C₀₋₄-alkyl, and C₃-C₆ cycloalkylaryl-C₀₋₂-alkyl are eachoptionally substituted with from one to three substituents eachindependently selected from R31.
 5. A compound as claimed by any one ofclaims 1 through 4 wherein X is —O—.
 6. A compound as claimed by any oneof claims 1 through 4 wherein X is —S—.
 7. A compound as claimed byclaim 1 wherein R4 is selected from the group consisting of C₁-C₅alkoxy, aryloxy, and arylC₀-C₄ alkyl.
 8. A compound as claimed by claim2 wherein Y is O.
 9. A compound as claimed by claim 7 wherein Y is C.10. A compound as claimed by claim 7 wherein Y is S.
 11. A compound asclaimed by any one of claims 1 through 4 wherein E is C(R3)(R4)A.
 12. Acompound as claimed by claim 11 wherein A is carboxyl.
 13. A compound asclaimed by claim 2 wherein R1 is H.
 14. A compound as claimed by claim13 wherein A is COOH and R1 is H.
 15. A compound as claimed by claim 14wherein R10 is haloalkyl.
 16. A compound as claimed by claim 11 whereinR10 is CF₃.
 17. A compound as claimed by claim 14, wherein R10 ishaloalkyloxy.
 18. A compound as claimed by claim 5 wherein R10 and R11are each independently selected from the group consisting of hydrogen,halo, oxo, C₁-C₆ alkyl, C₁-C₆ alkyl-COOR12″, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkyloxy.
 19. A compound as claimed by claim 5wherein R10 is selected from the group consisting of C₃-C₇ cycloalkyl,aryl-C₀₋₄-alkyl, aryl-C₁₋₄-heteroalkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, and aryloxy.
 20. A compound as claimed byclaim 5 wherein R8 and R9 are each independently selected from the groupconsisting of hydrogen and C₁-C₃ alkyl.
 21. A compound as claimed byclaim 5 wherein R3, and R4 are each independently selected from thegroup consisting of C₁-C₂ alkyl.
 22. A compound as claimed by claim 11wherein R3, and R4 are each independently selected from the groupconsisting of hydrogen and C₁-C₂ alkyl.
 23. A compound as claimed byclaim 6, wherein X—U is optionally substituted —S(CH₂)₂.
 24. A compoundas claimed by claim 11 wherein U is C₁-C₃ alkyl.
 25. A compound asclaimed by claim 24 wherein U is saturated.
 26. A compound as claimed byclaim 24, wherein U is substituted with C₁-C₃ alkyl.
 27. A compound asclaimed by claim 24, wherein U is substituted with arylC₁-C₄alkyl.
 28. Acompound as claimed by claim 24, wherein one carbon of the U group isreplaced with an —O—.
 29. A compound as claimed by claim 11 wherein R1is selected from the group consisting of phenyl and pyridyl.
 30. Acompound as claimed by claim 11 represented by the following StructuralFormula II:

wherein R33 is selected from the group consisting of hydrogen, C₁-C₃alkyl, and arylC₀-C₄ alkyl.
 31. A compound as claimed by claim 30wherein R33 is arylC₁-C₄ alkyl.
 32. A compound as claimed by claim 11represented by the following Structural Formula III:

R33 is selected from the group consisting of hydrogen, C₁-C₃ alkyl, andarylC₀-C₄ alkyl.
 33. A compound as claimed by claim 11 represented bythe following Structural Formula IV:


34. A compound as claimed by claim 11 wherein the headpiece of Formula Iis:

Compound Name

3-{2-Methyl-4-[5-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-phenyl}-propionic acid

3-{2-Methyl-4-[3-phenyl-5- (4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]- phenyl}-propionic acid

3-{4-[3,5-Bis-(4- trifluoromethyl-phenyl)- thiophen-2-ylmethoxy]-2-methyl-phenyl}-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- propoxy}-phenyl)-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- butoxy}-phenyl)-propionic acid

3-(2-Methyl-4-{2-methyl-1- [3-methyl-5-(4- trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}- phenyl)-propionic acid

3-(2-Methyl-4-{1-[3-methyl- 5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-2- phenyl-ethoxy}-phenyl)- propionic acid

3-(4-{1-[3-(2-Hydroxy- ethyl)-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]- ethylsulfanyl}-2-methyl- phenyl)-propionic acid


35. A compound as claimed by claim 11 wherein R4 is selected from thegroup consisting of C₁-C₅ alkyl, C₁-C₅ alkoxy, aryloxy, C₃-C₆cycloalkyl, and aryl C₀-C₄ alkyl, and wherein alkyl, alkoxy, cycloalkyland aryl-alkyl are each optionally substituted with one to three eachindependently selected from R26.
 36. A compound as claimed by claim 5wherein E is C(R3)(R4)A.
 37. A compound as claimed by claim 6 wherein Ais COOH.
 38. A compound as claimed by claim 1, wherein the compound isselected from the group consisting of(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-aceticacid,(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenoxy)-aceticacid,3-(2-Methyl-4-{2-[3-methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propylsulfanyl}-phenyl)-propionicacid, and(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-acetic.39. A compound as claimed by claim 1 that is(3-{2-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propoxy}-phenyl)-acetic.40. A compound as claimed by claim 1 wherein the compound is selectedfrom the group consisting of
 41. A compound as claimed by claim 1 whichis selected from the group consisting of{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenoxy}-aceticacid and3-{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-thiophen-2-ylmethoxy]-phenyl}-propionicacid.
 42. A compound as claimed by claim 11 which is the S conformation.43. A compound as claimed by claim 11 which is the R conformation.
 44. Apharmaceutical composition, comprising as an active ingredient, at leastone compound as claimed by claim 11 together with a pharmaceuticallyacceptable carrier or diluent.
 45. (canceled)
 46. A method of treatingdiabetes mellitus in a mammal, comprising the step of administering tothe mammal in need thereof, a therapeutically effective amount of atleast one compound of claim
 11. 47. A method of treating Metabolicsyndrome in a mammal, comprising the step of administering to the mammalin need thereof a therapeutically effective amount of at least onecompound of claim
 11. 48. A method of selectively modulating a PPARdelta receptor comprising administering a compound as claimed by claim11 to a mammal in need thereof.
 49. (canceled)
 50. A method of treatingatherosclerosis in a mammal, comprising the step of administering to themammal in need thereof a therapeutically effective amount of at leastone compound of claim
 11. 51. A method for treating or preventing theprogression of cardiovascular disease in a mammal in need thereofcomprising administering a therapeutically effective amount of acompound as claimed by claim
 11. 52. A method as claimed by claim 51wherein the mammal is diagnosed as being in need of such treatment. 53.A method of treating arthritis in a mammal, comprising the step ofadministering to the mammal in need thereof, a therapeutically effectiveamount of at least one compound as claimed by claim
 11. 54. A method oftreating demyelating disease in a mammal, comprising the step ofadministering to the mammal in need thereof, a therapeutically effectiveamount of at least one compound as claimed by claim
 11. 55. A method oftreating inflammatory disease in a mammal, comprising the step ofadministering to the mammal in need thereof, a therapeutically effectiveamount of at least one compound as claimed by claim
 11. 56. A method asclaimed by claim 53, wherein such mammal is diagnosed as being in needof such treatment.
 57. A compound as claimed by claim 11 for use as apharmaceutical.
 58. A compound as claimed by claim 11 wherein thecompound is radiolabeled.
 59. (canceled)
 60. (canceled)